Histological Subtypes and Divergent Differentiation of Urothelial Carcinoma: Histology, Genomics, and Management Implications.

Abstract

Histological subtypes and divergent differentiation are common in bladder cancer. Each subtype has distinct biology and clinical features. We aim to summarize pathology, molecular features, and outcomes of the most common bladder cancer subtypes to guide management. We performed a narrative review of cohort studies, clinical trials, and population-based analyses assessing morphology, immunophenotype, genomic alterations, and outcomes following various localized and systemic therapies in patients with bladder cancer subtypes. Histological subtypes are often understaged on transurethral resection of bladder tumor and commonly demonstrate lymph node metastasis, supporting early radical cystectomy (RC) even for certain clinically non-muscle-invasive bladder cancers. Small cell urothelial carcinoma (UC) consistently benefits from platinum/etoposide-based chemotherapy regimens, whereas predominant squamous, plasmacytoid, sarcomatoid, and micropapillary tumors demonstrate variable response rates to systemic therapies used in conventional UC. Trimodality therapy may approximate RC in locoregional control for small cell UC and appears inferior in cases with predominant squamous and adenocarcinoma. Genomic profiling highlights actionable alterations, albeit with unclear clinical implications. Immune checkpoint blockade and antibody-drug conjugates have been used sparingly against subtype bladder cancers and have anecdotally demonstrated activity across several subtypes. Histological subtypes and divergent differentiation of UC represent high-risk yet biologically distinct disease phenotypes that may not conform to the current "one-size-fits-all" treatment paradigm. More in-depth clinical and translational analyses with robust, adequately powered cohorts are required to further understand the clinical behavior of each unique bladder cancer subtype and to customize the optimal therapeutic strategies.