Genomic features of bladder neuroendocrine carcinoma with composite histology

Neuroendocrine carcinoma (NEC) is a rare and aggressive malignancy derived from multiple body parts, with the urogenital organs being the second-largest extrapulmonary sites. The detailed mechanism of bladder NEC pathogenesis remains unknown. We reviewed data from 23 patients diagnosed with NEC from urogenital organs (bladder and prostate) and conducted targeted sequencing of 523 cancer-related genes, focusing on bladder NEC. While 14 cases featured a pure NEC histology, the remaining nine cases included NEC histology mixed with other tumors, such as urothelial carcinoma (UC) or adenocarcinoma. Median overall survival in the entire cohort was 11.1 months, and survival curves were comparable between pure NEC and NEC of mixed appearance. Major mutations detected in the NEC component were in TP53 (38%), TERT promoter (31%), PIK3CA (25%), histone-modification genes (19%), and RB1 (19%). The BARD1 frameshift variant related to homologous recombination was also detected in one patient. More than half of the patients had a high total mutational burden (TMB; ≥10), including two with a TMB ≥45. Intriguingly, at least one identical gene variant in driver genes was detected between NEC and non-NEC (UC) components in the four bladder specimens analyzed. These results highlight the possibility of shared genetic background between bladder NEC and UC. Additionally, several cases harbored druggable gene alterations as presented by TMB-high. Our presentation of the histopathological and molecular features of NEC may help clarify the underlying mechanisms and contribute to efficient treatment of the disease.