Aims: Tumour budding (TB), groups of up to 4 cells beyond the invasion zone, is a prognostic biomarker in various cancers. Their role in gastric, oesophageal and gastroesophageal junction (GOC) is poorly understood. The urokinase plasminogen activator system (uPAS) and epithelial to mesenchymal transition (EMT) assist tumour invasion and formation of distant metastasis. The uPAS membrane receptor, uPAR, is strongly associated with the mesenchymal phenotype of EMT and may be an EMT driver. E-cadherin is a classical marker of the epithelial phenotype of EMT. We aimed to assess the expression of uPAR and E-cadherin in GOC TB.
Methods: Patients underwent GOC surgery between 2013-2021 at the Illawarra Shoalhaven Local Health District, NSW. Assessment of TB was conducted using Haematoxylin and Eosin (H&E) staining and were scored as per the international tumour budding cancer consensus guidelines. Areas showing the highest TB were sectioned for uPAR and E-cadherin immunohistochemistry. We used Pearson correlation coefficient, Kaplan Meier method and log-rank test for statistical analysis.
Results: TB was assessable by H&E for 65 patients, with uPAR in 57 cases and E-cadherin in 45 cases. TB was not predictive of long-term overall survival (OS), the best cut off value being 4 TBs (p=0.2). There was excellent correlation of H&E stained and counted TBs and uPAR+ TBs (R2=88%). More than 8 uPAR+ TBs was significantly associated with worse OS (median 24 vs 42 months; p=0.01). Strong E-cadherin expression showed a non-significant trend to improved OS (median 47 vs 29 months; p=0.3). A combined high uPAR and low E-cadherin score (i.e., mesenchymal-like cells), tended for shorter OS (median 18.5 vs 47 months; p=0.3).
Conclusions: Despite standard TB reporting not showing OS discrimination, uPAR shows excellent potential as a predictive biomarker. In this pilot cohort, combination of uPAR and E-cadherin showed potential to determine poor prognostic patients.