Introduction & Objectives: The long term increased risk of secondary malignancy is a well-documented late effect of radiation therapy. However, the incidence, time interval, anatomic site and histopathology are not well studied. As our knowledge of molecular subtyping of urothelial carcinoma (UC) has advanced, we sought to characterize the secondary malignancies in a cohort of patients from 1998-2016.
Materials & Methods: Among a total of 4570 patients who have undergone brachytherapy, a cohort of 72 patients have been diagnosed with secondary bladder cancer. Slides were reviewed, and site and pathologic features were recorded. Individual slides were stained for GATA3 and CK5/6 and classified as luminal and basal subtypes.
Results: The average time interval between brachytherapy and bladder cancer development was 6.3 years (range 1-17). The most common sites of involvement were the bladder neck (26%) and trigone (25%). Of all cases, 70% (51/72) were high-grade, 25% (18/72) were muscle-invasive, and 57% (41/72) were non-invasive (Ta). 19% of cases showed variant morphology, including small cell carcinoma (n=3), sarcomatoid carcinoma (n=1), squamous cell carcinoma (n=2), UC with divergent differentiation (n=6), nested variant (n=1) and adenocarcinoma arising from the prostatic urethra (n=1), Molecular subtyping by immunohistochemistry demonstrated that 72% of cases were of luminal subtype. All of the basal cases were high-grade and invasive (T1 or greater), whereas 60% of the luminal cases were high-grade and 29% were invasive. The cases that were more likely to be radiation-induced, based on anatomic site and time interval, were associated with a higher risk of invasive disease (70% vs 34%, p=0.01).
Conclusions: The majority of bladder cancers post-brachytherapy in this cohort were of high grade and low stage at diagnosis, most of them demonstrating luminal immunophenotype. A significant number of variant morphologies are seen, each demonstrating a specific immunophenotype.
