Bladder cancer is the fourth most common cause of cancer in American males and is the 10th most common cancer worldwide, representing approximately 3% of all cancers.1 Bladder cancers encompass a broad spectrum of lesions, with oncologic behavior driven by grade, stage, variant morphology, and clinical location. While much of the therapy for bladder cancer is based on clinical and histopathological evaluation, recent work on immunohistochemical biomarkers and molecular categorization has added new ways to classify bladder cancer based on ancillary tests.

The advent of immunotherapy and radiation treatment options for this disease further expanded the need for robust characterization of these lesions and sparked an interest in biomarkers that can predict therapeutic response. In this chapter, we will summarize the histopathological heterogeneity of bladder cancers, discuss staging and key distinctions between muscle-invasive and non-muscle-invasive bladder cancer at the pathological and molecular level, and highlight emerging biomarkers that could potentially predict response to radiation therapy in bladder cancer.