TUMOR BUDDING AT THE CROSSROADS OF HISTOPATHOLOGY AND MOLECULAR ONCOLOGY IN COLORECTAL CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Background: Tumor budding (TB), defined as the presence of isolated single tumor cells or small clusters of fewer than five cells at the invasive front of colorectal carcinoma, has emerged as a promising prognostic biomarker reflecting tumor aggressiveness and metastatic potential. Increasing evidence suggests that tumor budding represents the histomorphological manifestation of epithelial-mesenchymal transition (EMT) and is closely associated with molecular pathways involved in colorectal cancer (CRC) progression. However, the prognostic significance of TB and its relationship with key molecular alterations remain incompletely understood.

Objective: To systematically evaluate the prognostic impact of tumor budding in colorectal cancer and investigate its association with major molecular biomarkers, including microsatellite instability (MSI), KRAS, BRAF, TP53 mutations, Wnt/β-catenin signaling, and EMT-related markers.

Methods: A systematic review and meta-analysis were conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library databases were searched from January 2000 to January 2026. Studies assessing tumor budding in histologically confirmed colorectal cancer and reporting clinicopathological, survival, or molecular outcomes were included. Data extraction and quality assessment using the Newcastle-Ottawa Scale were performed independently by two reviewers. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated using random-effects models.

Results: A total of 42 studies involving 18,764 patients met the inclusion criteria. High-grade tumor budding was significantly associated with adverse pathological features, including lymph node metastasis (OR = 3.68, 95% CI: 2.91-4.65), lymphovascular invasion (OR = 3.41, 95% CI: 2.71-4.28), perineural invasion (OR = 2.95, 95% CI: 2.12-4.11), and distant metastasis (OR = 4.12, 95% CI: 3.16-5.37). Survival analysis demonstrated significantly poorer outcomes among patients with high-grade budding, including overall survival (HR = 2.14, 95% CI: 1.85-2.48), disease-free survival (HR = 2.31, 95% CI: 1.98-2.69), cancer-specific survival (HR = 2.47, 95% CI: 2.01-3.03), and recurrence-free survival (HR = 2.21, 95% CI: 1.78-2.75). Molecular analyses revealed significant associations between high tumor budding and KRAS mutations (OR = 1.89, 95% CI: 1.42-2.51), TP53 alterations (OR = 2.06, 95% CI: 1.55-2.73), and nuclear β-catenin accumulation (OR = 2.71, 95% CI: 2.02-3.64). Conversely, microsatellite instability-high tumors demonstrated significantly lower rates of high-grade budding (OR = 0.54, 95% CI: 0.41-0.72). No significant association was observed between tumor budding and BRAF mutation status (OR = 1.12, 95% CI: 0.81-1.56). High-grade budding was consistently associated with reduced E-cadherin expression and increased expression of mesenchymal and EMT-related markers, including vimentin, Snail, Twist, and ZEB1.

Conclusion: Tumor budding is a powerful independent predictor of poor prognosis in colorectal cancer and serves as a histological surrogate of molecular mechanisms underlying invasion and metastasis. Its strong associations with EMT activation, Wnt/β-catenin signaling, KRAS mutations, and TP53 alterations highlight its role as a critical bridge between histopathology and molecular oncology. Incorporation of tumor budding into routine pathology reporting and integrated histomolecular risk stratification models may improve prognostic assessment and support personalized therapeutic decision-making in colorectal cancer.