Urothelial carcinoma: variant histology, molecular subtyping, and immunophenotyping significant for treatment...

Although urothelial carcinoma (UC) has been recognised as a homogenous disease entity until recently, it exhibits widely diverse histological variants. Recent studies have revealed that some histological variants may serve as markers of very high risk for advanced cancers and poor prognoses. Certain histological variants can generate a pathological T stage, which may result in unnecessary surgery. Though platinum based chemotherapy is the standard treatment, the use of immune checkpoint inhibitors (ICIs) for UC treatment has become a major trend in oncology. UCs showing specific histological variants have responded exceptionally well to chemotherapy and ICIs. Currently, molecular studies base molecular classification on gene expression profile signatures in order to make diagnoses or predict responses to chemotherapies and ICIs. Notably, some histological variants correlate with specific molecular subtypes. The usefulness of immunophenotyping for classification purposes was recognised only recently. Immunophenotypes are classified into three categories according to lymphocyte distribution in or around the cancer cell nest: desert, excluded, and inflamed. This immunophenotyping has been increasingly shown to be of value in predicting the response to ICIs. This review describes the morphological characteristics of histological variants as well as the advantages and limitations in determining them, with particular reference to clinical benefits. Subsequently, we describe the concept of molecular classification and immunophenotypes, and their morphological features, which are easily interpreted and amenable to daily practice via hematoxylin and eosin staining. We also consider the clinical advantages, limitations, and issues encountered while using these in routine clinical practice.