Plasmacytoid Urothelial Carcinoma, a Chemosensitive Cancer with Poor Prognosis, and Peritoneal Carcinomatosis

Pathological evaluation of bladder cancer typically reveals great tumour heterogeneity, and therefore the common observation of urothelial carcinoma exhibiting a wide variety of histopathological patterns is not surprising. Some of these patterns are so distinctive that they have been recognised as specific variants of urothelial carcinoma. Classifications have recently been revised in the 2016 World Health Organisation (WHO) classification of tumours of the urinary system and male genital organs. The current WHO classifications clarify terminological issues and provide better definition criteria, but also incorporate some new entities. Many of these variants have important prognostic or therapeutic implications worth knowing by the urologist and oncologist, but also represent diagnostic challenges in daily pathology practice. This review will discuss the features of variants of urothelial carcinoma in the context of our current clinical practice. Histological variations and new entities of bladder cancer not included in the current WHO classification of urothelial tumours will be briefly discussed.

Variants and new entities of bladder cancer.

Objectives To evaluate pathologic and survival outcomes among patients with variant histology (VH) urothelial carcinoma of the bladder. Methods A retrospective review of an institutional database was performed to identify all patients who underwent radical cystectomy with curative intent for urothelial carcinoma between 2008 and June 2013. VH was assigned by genitourinary pathologists. Descriptive statistics comparing clinicopathologic outcomes were performed using the Pearson chi-square test and analysis of variance. Survival was evaluated using the Kaplan-Meier methodology and the Cox proportional hazards regression. Results In total, 624 patients were identified. Overall, 26% ( n = 162) had VH, with the most common being squamous differentiation ( n = 68), micropapillary variant (MPV, n = 28), plasmacytoid variant (PCV, n = 25), and sarcomatoid variant ( n = 15); 64% of MPV and 72% of PCV had positive lymph nodes. Compared with 8% of patients with a non VH, 44% of those with VH were categorized as pT4 ( P P = 0.004; odds ratio = 2.42, 95% CI: 1.33–4.42; P = 0.004, respectively). There was no difference in risk of mortality associated with squamous differentiation or sarcomatoid variant ( P >0.05 each). Conclusions MPV and PCV are associated with increased risk of mortality. Improved recognition of VH will enable larger cohorts of study and better prognostic understanding of the significance of specific VH involvement.

Contemporary bladder cancer: Variant histology may be a significant driver of disease

Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.

Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes.

Background
Since the definition of different histologic subtypes of urothelial carcinomas by the World Health Organization (WHO) 2004 classification, description of molecular features and clinical behavior of these variants has gained more attention.

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Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy

The WHO 2004 classification defines new histological and molecular variants of urothelial carcinoma. However, there are limited data available on the clinicopathological characteristics or prognosis of these variants. We present histopathological, molecular and clinical data of 32 plasmacytoid carcinomas of the bladder (PUC) showing that PUC is a high-grade tumor with molecular features of aggressive urothelial carcinoma, usually diagnosed in advanced pathological stage (64% pT3, 23% pT4) showing metastases in 60% of the patients. Average survival of our cohort of PUC treated with radical cystectomy and adjuvant chemotherapy was lower than what is typically seen for comparable conventional urothelial carcinomas. Eighty-seven percent of the PUCs showed a negative or strongly reduced membranous staining of E-cadherin. β-Catenin staining was negative in 22.5%, and 16.7% of the remaining tumors showed nuclear accumulation. Aberrant CK20 expression (negative or >10% of cells stained) and negative CK7 staining was found in 100% and 22.6%, respectively. Ninety-seven percent revealed positive staining for PAN-CK. CD138 was positive in 78%, whereas MUM-1 expression was negative in all cases. Multitarget fluorescence in situ hybridization showed all PUCs to be highly aneuploid and polysomic. Deletions on chromosome 9p21 seem to play an important role in this variant. FGFR3 and PIK3CA mutation analyses yielded no mutations in any of the PUCs analyzed. TP53 mutation analysis showed mutations in 29%. In summary, PUC is an aggressive variant of bladder cancer with molecular features of advanced bladder cancer and evidence of WNT pathway activation in some of the cases.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.25700

Mathilde Sibonye

Papers

The plasmacytoid carcinoma of the bladder--rare variant of aggressive urothelial carcinoma.