Evolution of Urothelial Bladder Cancer in the Context of Molecular Classifications

Abstract

Bladder cancer is a heterogeneous disease that is not depicted by current classification systems. It was originally classified into non-muscle invasive and muscle invasive. However, clinically and genetically variable tumors are summarized within both classes. A definition of three groups may better account for the divergence in prognosis and probably also choice of treatment. The first group represents mostly non-invasive tumors that reoccur but do not progress. Contrarily, the second group represent non-muscle invasive tumors that likely progress to the third group, the muscle invasive tumors. High throughput tumor profiling improved our understanding of the biology of bladder cancer. It allows the identification of molecular subtypes, at least three for non-muscle invasive bladder cancer (Class I, Class II and Class III) and six for muscle-invasive bladder cancer (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous and neuroendocrine-like) with distinct clinical and molecular phenotypes. Molecular subtypes can be potentially used to predict the response to treatment (e.g., neoadjuvant chemotherapy and immune checkpoint inhibitors). Moreover, they may allow to characterize the evolution of bladder cancer through different pathways. However, to move towards precision medicine, the understanding of the biological meaning of these molecular subtypes and differences in the composition of cell subpopulations will be mandatory.

Association between blood pressure and BMI with bladder cancer risk and mortality in 340,000 men in three Swedish cohorts

“…However, grading, the extent to which the tumor cells are similar in appearance and function to the normal cells, is another dimension to measure tumor aggressiveness, harboring additional information especially for NMIBC and risk of progression 6 . Also biologically, a two‐pathway theory has been proposed with stratification in NMIBC and MIBC 7 . Clinically, stratification in NMIBC and MIBC occurs in a majority of patients associated with preserving versus radical treatment, respectively.…”

Educational Case: Bladder Urothelial Cell Carcinoma TNM Stage, Prognosis and Management

“…All flat CIS urothelial lesions (Tis) are considered high grade and should be investigated for the characteristic genetic mutations and histopathologic features of nuclear and cellular atypia. 8 , 10 Histopathologic examination from TURBT of the lesion would show a flat lesion with full thickness cytological atypia and an intact basement membrane.…”

“…8 The nonpapillary pathway, flat dysplasia, and/or CIS (25%-30%), as seen in this patient ( Figure 1 ) are the precursors of most muscle invasive bladder cancer (MIBC) and have a rapid progression and high metastatic potential and a high mortality. 10 Loss of heterozygosity on chromosome 9p or 9q leading to deletion of CDKN2A is the most common alteration and may be seen in both papillary (exophytic) and flat (endophytic) bladder cancer morphology. 11 , 12 Fluorescence in situ hybridization a molecular diagnostic technique to detect chromosomal del 9p(21) abnormality in urine samples from patients with atypical, suspicious, and negative cytopathology.…”

“…All flat CIS urothelial lesions (Tis) are considered high grade and should be investigated for the characteristic genetic mutations and histopathologic features of nuclear and cellular atypia. 8,10 Histopathologic examination from TURBT of the lesion would show a flat lesion with full thickness cytological atypia and an intact basement membrane. A T2 lesion is considered invasive because it disrupts the basement membrane and infiltrates the muscularis layer of the bladder wall and is divided into pT2a (tumor invading superficial inner half of the muscularis propria) or pT2b (tumor invading deep, to the outer half of the muscularis propria) based on the extent of muscularis invasion.…”

Characteristics of upper urinary tract urothelial carcinoma in the context of bladder cancer: a narrative review

“…This may help to refine the two-pathway model and to explain the evolution of bladder cancer. Contrarily, class III tumors presented with a basal like phenotype and did not show similarities to molecular characteristics identified in MIBC (50). The Lund group was the first to attempt a molecular classification system in BC ( 51).…”