Tumor Budding in Colorectal Cancer: Biological Basis, Clinical Risk Stratification, and Digital Pathology

Tumor budding, defined as single tumor cells or clusters of up to four cells at the invasive front, is a morphological marker of tumor-cell dissociation and stromal invasion in colorectal cancer. Standardization by the International Tumor Budding Consensus Conference (ITBCC) established a reproducible hematoxylin-and-eosin-based method and enabled broader incorporation of budding into pathology reporting and clinical risk assessment. Intermediate- and high-grade budding are associated with lymph node metastasis in pT1 colorectal cancer, while high-grade budding identifies a subgroup of stage II colon cancers with increased recurrence risk. Adverse prognostic associations have also been reported in stage III disease and in rectal cancer after neoadjuvant therapy, although evidence that budding predicts benefit from a specific treatment is still insufficient. At the biological level, budding is linked to partial epithelial-mesenchymal transition, altered cell adhesion, cytoskeletal remodeling, and interactions with fibroblasts, extracellular matrix, and immune cells. Digital pathology and artificial intelligence may improve hotspot selection, quantification, and spatial characterization, but their clinical use depends on external validation, control of domain shift, and continued pathologist oversight. Tumor budding is therefore best interpreted as a complementary morphological biomarker alongside TNM stage, established histopathological risk factors, molecular features, and clinical context.