Peritumoral Malignant Cellular Foci Performs Better Than Tumor Budding and Poorly Differentiated Cluster in Risk Stratification of Lymph Node Metastasis in pT1 Colorectal Cancer

As biomarkers separated by the arbitrary 5-tumor-cell cutoff at the tumor invasive front, tumor budding (TB) and poorly differentiated clusters (PDC) are recognized as high-risk factors for lymph node metastasis (LNM) in pT1 colorectal cancer (CRC). Nonetheless, relevant findings remain inconsistent. Furthermore, the association between the tumor invasive front biomarker and D3 LNM in pT1 CRC remains unknown. To identify a biomarker that captures the full morphologic spectrum and eliminates the need for such cutoffs at the tumor invasive front for predicting LNM, particularly D3 LNM, in pT1 CRC, we defined peritumoral malignant cellular foci (PMCF) as nonglandular foci composed of ≥1 tumor cell at the tumor invasive front. After enrolling 2611 endoscopically or surgically resected pT1 CRC patients from 6 high-volume Chinese institutions, we found that neither TB nor PDC exhibited a consistent independent association with LNM across the training and validation cohorts. In contrast, PMCF emerged as an independent risk factor with superior risk stratification of LNM in both cohorts (P<0.05). The association between PMCF and LNM remained significant in subgroup analyses stratified by age, sex, tumor location, and BMI (P<0.05). Moreover, PMCF correlated with a greater number of metastatic lymph nodes and exhibited a stronger association with D3 LNM than with D1 and D2 LNM (P<0.05). In conclusion, PMCF not only suggests additional radical surgery after endoscopic resection in pT1 CRC, but may also indicate D3 lymph node dissection. PMCF provides an evidence-based rationale to optimize surgical decision-making in pT1 CRC.