The molecular pathological basis and potential clinical applications of 'zero-budding' status in stage II colorectal cancer

In the personalized management of stage II colorectal cancer (CRC), traditional TNM (Tumor, Node, Metastasis) staging has limited ability to accurately stratify the risk of postoperative recurrence. Consequently, oncologists frequently face a major therapeutic dilemma when determining the use of adjuvant chemotherapy in these patients. Although tumor budding (TB) has been incorporated into international clinical guidelines as an independent prognostic marker associated with invasive potential, the conventional International Tumor Budding Consensus Conference classification system is primarily based on routine hematoxylin and eosin (H&E) staining. Furthermore, this framework classifies tumors with 0-4 buds into a single low-risk category termed Bd1. This classification may obscure important biological differences between tumors with complete absence of cellular dissociation and those already showing early invasive activity. This review proposes separate diagnostic recognition of the 'zero-budding' (Bd0) category. Recent large-scale cohort studies and retrospective analyses support that Bd0 status, particularly when confirmed by pan-cytokeratin immunohistochemistry, is associated with an extremely high negative predictive value for postoperative recurrence. At the subcellular level, the Bd0 category may reflect sustained suppression of the epithelial-mesenchymal transition process. Mechanistically, this relatively non-invasive category may be maintained by preservation of the EBP50 scaffold, which stabilizes the membranous E-cadherin/beta-catenin complex and suppresses nuclear translocation of Wnt/beta-catenin. Bd0 is also strongly associated with the deficient mismatch repair microenvironment, in which high tumor mutational burden may promote enhanced CD8+ T cell-mediated immune surveillance capable of eliminating disseminating tumor cells before morphologic budding becomes detectable. This review summarizes the evolution of TB assessment, reviews the available clinical evidence supporting Bd0, evaluates emerging diagnostic approaches, and discusses the underlying molecular mechanisms.