Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer

Abstract

Background: Urothelial bladder cancer (UBC) is a highly prevalent disease in North America, however its optimal management remains elusive. The contribution of B cell associated responses is poorly understood in bladder cancer. Lymphoid neogenesis is a hallmark of an active immune response at tumor sites that sometimes leads to formation of tertiary lymphoid structures (TLS) that resemble germinal centers formed in secondary lymphoid organs. Objective: This study was conducted with an aim to investigate the presence and characteristics of TLS in UBC with a focus to compare and contrast the TLS formation in treatment naive low grade non-muscle invasive (NMIBC) and muscle invasive bladder cancers (MIBC). Methods: The study cohort consisted of transurethral bladder resection tumour (TURBT) specimens from 28 patients. Sections showing lymphoid aggregates in hematoxylin and eosin (H&E) stained TURBT specimens were further subjected to multi-color immunohistochemistry using immune cell markers specific to CD20+ B cells, CD3+ and CD8+ T cells, PNAd+ high endothelial venules, CD208+ mature dendritic cells, CD21+ follicular dendritic cells to confirm the hallmarks of classical germinal centers. Results: Our pilot study investigating the presence of TLS in bladder cancer patients is the first to demonstrate that well-formed TLS are more common in aggressive high grade MIBC tumors compared to low grade NIMBC. Conclusions: These novel findings suggest B cell mediated anti-tumour humoral immune responses in bladder cancer progression.