PAX8-positive conventional urothelial carcinomas of the urinary bladder and their distinct molecular profiles - A clinicopathologic study of 101 consecutive cases with next-generation sequencing in 20 cases.
Summary
This retrospective study investigated the frequency and molecular profiles of PAX8-positive conventional urothelial carcinomas (UCs) of the urinary bladder. Out of 101 cases, 10% were found to be PAX8-positive by immunohistochemistry. Next-generation sequencing (NGS) was performed on 20 cases, including all PAX8-positive UCs. The findings revealed that PAX8-positive UCs frequently harbored TERT promoter mutations, TSC1 alterations, NOTCH1 loss, and WT1 loss, while notably lacking RB1 loss, distinguishing them from PAX8-negative UCs. These results indicate a distinct molecular signature for PAX8-positive UCs, emphasizing the need for careful diagnostic interpretation of PAX8.
Analysis
🔴 CLINIQUE: This retrospective study highlights a potential diagnostic pitfall: PAX8 positivity, often used to differentiate UCs from other tumors, can occur in 10% of conventional bladder UCs. This necessitates cautious interpretation of PAX8 immunohistochemistry when UC is in the differential diagnosis. The integration of next-generation sequencing (NGS) could become a valuable tool to refine differential diagnosis by identifying the distinct molecular profile associated with PAX8-positive UCs. Clinical impact could be seen in the medium term (3-5 years) if these distinct molecular profiles lead to specific prognostic or therapeutic implications. 🟢 BIOMOL: The discovery of a distinct molecular profile for PAX8-positive UCs is significant. All PAX8-positive cases exhibited TERT promoter mutations, and TSC1 alterations, NOTCH1 loss, and WT1 loss were more frequent, with a notable absence of RB1 loss. These findings were enabled by the use of immunohistochemistry (IHC) for initial screening and next-generation sequencing (NGS) for molecular characterization. This profile could serve as a diagnostic or prognostic biomarker and potentially guide translational research towards specific therapeutic targets for this patient subgroup.