Morphological correlation of urinary bladder cancer molecular subtypes in radical cystectomies

Several molecular subtypes of bladder cancer were identified with differing clinical behavior and responses to platinum-based chemotherapy. But so far, their urothelial histomorphologic features, besides association with some variant histologies, have remained fully undefined. We sought to characterize the histological features of genomically classified bladder cancers more extensively to tumor in radical cystectomy (RC) specimens. Forty-eight bladder cancers submitted to The Cancer Genome Atlas (TCGA) were classified using the BASE47 genomic classifier into luminal subtype (LS) (14 cases), basal subtype (BS) (18 cases), and claudin-low subtype (CLS) (16 cases), and TCGA samples and the corresponding RC specimens were histologically assessed. Marked pleomorphism was more extensive in CLS tumors (87.5% had >15% extent) than in LS tumors (21.4%) (p = 0.0006), whereas the extent in BS tumors was in between LS and CLS tumors. Pleomorphism in distant carcinoma in situ appeared to correlate with that in the main tumor. Ki-67 proliferation was higher in CLS tumors (mean = 61%) than in LS tumors (mean = 29%) or BS (mean = 30%) (p < 0.001). Squamous differentiation was more extensive in BS and CLS tumors (38.2% of BS and CLS tumors versus 7.1% of LS tumors had >30% squamous, p = 0.040). Sarcomatoid change was present in BS and CLS tumors only. The micropapillary variant was identified in LS (3/14) and BS (4/18) tumors only. Histologic features associated with aggressiveness (eg, marked pleomorphism, high proliferation, and sarcomatoid change) are enriched in CLS tumors, correlating with its known poorer outcome that may provide hints in their microscopic distinction. Features more associated with BS than with LS tumors (eg, squamous, marked pleomorphism, and sarcomatoid change) are also identified or enhanced in CLS tumors, supporting the genomic findings suggesting CLS tumor as a hyperbasal form of BS tumor.