Management options Variant histology in Bladder Cancer

Bladder cancers have the unique ability for variant histomorphological characteristics. The estimated incidence of variant histology in TURBT specimens  ranges from 6-33% and up to 44% of histologic variants are missed by community pathologists. The most commonly missed subtypes are plasmacytoid and micropapillary variants.

The WHO updated the histological classification of BC in 2022 and categorised variants into UC with nonconventional histological subtypes, UC with divergent differentiation, squamous cell carcinomas, adenocarcinoma and neuroendocrine neoplasms.

All histological variants are considered aggressive, high-grade carcinoma. Majority of the variants are muscle invasive at presentation, with no more than 15–30% being non-muscle invasive. According to the Updated WHO 2022 classification, the term variant should be avoided because it is commonly used for genomic alterations.

Histological subtype:  specific histology features that are urothelial in appearance but have distinct architectural features (e.g., micropapillary or plasmacytoid growth pattern).

Divergent differentiation: histology is no longer urothelial but exhibits a different histogenesis such as squamous, glandular or trophoblastic.

Both subtypes and divergent differentiation may be found within a single tumor.

BC variants represent a diverse group of tumours with nuanced prognostic, diagnostic, and management implications. Specialised uropathology assessment guided by the 2022 WHO classification is strongly recommended. All cases warrant discussion in multidisciplinary team meetings. Molecular profiling and clinical trial participation are key to optimising classification and treatment of these patient. 

Table 1: Management options for Histological subtypes of UC

	Micro papillary UC	Sarcomatoid UC	Plasmacytoid UC	Squamous differentiation	Glandular differentiation
Incidence	2-5%	0.3%	1%	30-40% of non conventional UC	18% of non conventional UC
Treatment considerations	Upfront RC preferred for NMIBC over BCG (CSS- 72% vs 60%) MIBC treatment similar to conventional US Neo-adj chemo - no effect on OS	Radical cystectomy Poor response to chemotherapy Interest in IORT in the peri-operative setting 5yr CSS - 28.4% (across all stages)	Radical cystectomy Characteristic intra-peritoneal mets Poor outcomes following RC (median OS - 17.7m) No influence of systemic treatment on survival of outcomes	Similar to conventional UC Associated with recurrence and progression	Similar to conventional UC Similar recurrence free and overall survival

Table 2: Management options for Divergent differentiation of bladder cancers

	Squamous cell carcinoma	Adenocarcinoma of bladder	Small cell bladder cancer
Incidence	5%	0.5-2%	0.5-1.2%
Treatment considerations	Localised setting: Low chemo sensitivity Upfront RC is standard of care Chemo-RT may be considered of surgery unsuitable Consider post-operative RT if margin are positive Advanced setting: Clinical trial enrolment and molecular analysis are preferred	Localised setting: Upfront RC is standard of care For urachal adenocarcinoma, consider partial cystectomy with excision of the urachal remnant LND only prognostic role, does not improve OS Omphalectomy - improves OS and CSS Advanced setting: FOLFOX or TIP chemotherapy	Localised setting: NAC followed by RC or RT are the main recommendation  Prophylactic intracranial RT is not encouraged Advanced setting: EP is the SOC, ifosfamide and doxorubicin with EP is an alternative