Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation

Abstract

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a “consensus” classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping.

HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

“…HER2 alterations have been extensively studied in MPCs [ 71 , 72 , 73 ], with rates of overexpression and amplification in up to 75% and 42% of cases, respectively [ 74 , 75 ], supporting the classification of MPCs as luminal tumors [ 7 , 71 ]. Two studies comparing stage-matched MPC to conventional BC reported higher amplification rates in the first group (12% and 15% vs. 6% and 9%, respectively) [ 70 , 73 ].…”

“…The biological and clinical heterogeneity of BC has led several researchers to develop classification schemes able to mirror this variability and translate it into distinct subtypes according to their mRNA expression profiles in the last decade. The next steps were to combine these findings into a consensus classification and to implement such molecular subtyping as a risk-stratification tool in routine practice, using IHC in order to assess subtype-specific biomarkers at the protein level [ 7 , 8 ].…”

“…As far as we know, BC is a heterogeneous disease from a molecular standpoint as well, resulting from a complex multi-step carcinogenesis that includes several changes involving genes and molecular pathways with specific functions in tumor development and progression. In an attempt to catch this biological variability, several efforts have been made over the last decade to develop of a molecular classification encompassing a discrete category of BC harboring different clinical and prognostic features, matching their DNA and RNA profiles [ 6 , 7 , 8 , 9 ]. In routine practice, current risk assessment models in NMIBC, as well as predictive/prognostic systems in MIBC, are based on clinical and histopathological features [ 10 ].…”

Prognostic Value of P63 Expression in Muscle-Invasive Bladder Cancer and Association with Molecular Subtypes—Preliminary Report

“…In the last decade, several studies based on transcriptional analysis have resulted in different attempts at molecular subtyping of MIBCs, all of them sharing the top-level distinction into luminal and basal tumor types, as highlighted by a recent consensus classification [ 6 , 7 ], with each subtype being associated with peculiar clinical features as well as variable sensitivity to treatments. Immunohistochemical (IHC) antibodies have been described as effective surrogate markers for both luminal (CK20, GATA3) and basal (high-molecular-weight cytokeratins, such as CK5/6 and CK14) tumors, in order to translate research findings into routine clinical practice [ 8 , 9 ].…”

Clinicopathological Features and Survival Analysis in Molecular Subtypes of Muscle-Invasive Bladder Cancer

“…The latter has activated PPAR-γ and FGFR3 mutations, with enriched epithelial markers, and a good clinical prognosis, whereas basal tumors are associated with EGFR regulon activity, usually present at an advanced stage, and have the worst clinical prognosis [ 10 ]; nevertheless, they seem to be more sensitive to neoadjuvant cisplatin-based chemotherapy than luminal MIBCs [ 11 , 12 ]. The routine performance of molecular analysis in current practice is undermined by technical and economic issues; thus, immunohistochemical (IHC) surrogates for molecular profiling have been identified by validating the consistency between mRNA expression profiles and the expression of immunohistochemical markers [ 13 , 14 ].…”