Clinical and biological implications of fragmented response in rectal cancer after neoadjuvant chemoradiotherapy

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer. Tumour regression patterns after nCRT are heterogeneous, with current tumour regression grading (TRG) systems (i.e. Mandard, Dworak, Ryan) focusing on residual tumour versus fibrosis. However, these factors do not account for fragmentation, a frequent and clinically relevant response pattern. METHODS: A review of literature was performed. This review synthesizes current evidence on the definition, histopathology, biology and clinical implications of tumour fragmentation in rectal cancer. RESULTS: Fragmentation is defined as scattered clusters of viable tumour cells within fibrotic stroma, a tumour response that contrasts with concentric tumour shrinkage. It has been linked to an increased likelihood of residual disease, lymph node metastases, positive margins, and local recurrence. From a biological standpoint, fragmentation is indicative of clonal selection, epithelial-mesenchymal transition, stromal activation and immune suppression, suggesting a distinct entity rather than a partial regression. Current TRG and TNM systems are unable to capture this heterogeneity, which may limit the accuracy of prognosis and organ-preservation decision-making. CONCLUSION: It is essential to recognize fragmentation as a discrete clinical and biological response pattern. Future studies should integrate radiological, pathological, and molecular biomarkers to better understand this response pattern.