Analysis of HER2 Expression in Different Histological Subtypes and IHC-Based Molecular Variants of Muscle-Invasive Bladder Carcinoma

<i>Background and Objectives</i>: Urothelial carcinoma of the urinary bladder is a heterogeneous disease with diverse morphological and molecular characteristics. This study aims to analyze the expression of HER2 in 100 consecutive cases of muscle-invasive bladder carcinoma (MIBC), with a special attention to the different histological subtypes and consensus molecular variants determined by IHC methods. <i>Materials and Methods</i>: A retrospective single-center study was conducted on 100 consecutive cases of MIBC (2021-2024). HER2 status is assessed by immunohistochemistry (IHC) (scores 0, 0+, 1+, 2+, 3+), and the results are compared with the published data. <i>Results</i>: We have established that over half of the tumors (~60%) show some level of HER2 expression, with strong expression (3+) present in 25%. There are significant differences among the IHC-based molecular variants: luminal tumors, including papillary tumors, exhibit a frequent HER2 overexpression, whereas those with a basal immunophenotype (e.g., squamous, sarcomatoid variants) are almost entirely HER2-negative. The micropapillary subtype and some other rare subtypes can also express HER2. <i>Conclusions</i>: HER2 is an important biomarker with heterogeneous expression in urothelial carcinoma of the bladder. The present study showed that the frequency and level of HER2 expression vary substantially among different histopathological subtypes and molecular variants. In therapeutic terms, interest in HER2 as a target is growing-new antibody-drug conjugates show a promising activity even in cases with low HER2 expression, which will likely lead to the integration of HER2-directed therapies and routine testing in the future.