Distance-based evaluation of tumor budding in colorectal cancer

Tumor budding is an established adverse prognostic factor in colorectal cancer (CRC), based on the number of isolated single tumor cells or small tumor cell clusters at the invasive front. While bud counts are well studied, the prognostic significance of the spatial distribution and distance of tumor buds away from the tumor bulk is unclear. We defined TB-distance as the average distance from the tumor bulk to the three farthest tumor buds and evaluated its clinicopathologic and prognostic associations in two independent CRC cohorts (N = 776 and N = 1,100). Using a cohort-derived cutoff, high TB-distance (≥ 123 µm) was significantly associated with adverse tumor characteristics, including high grade, advanced disease stage, lymphovascular invasion, high conventional tumor budding grade, and MMR proficient status (p < 0.003 for all). High TB-distance was also associated with shorter cancer-specific survival (Cohort 1: multivariable HR (high vs. low) 1.47, 95% CI 1.04-2.09, p = 0.030; Cohort 2: multivariable HR 1.34 95% CI 1.04-1.74, p = 0.026). However, TB-distance did not provide additional prognostic information within conventional tumor budding grade strata or when modeled alongside tumor budding. These findings indicate that high TB-distance is associated with aggressive tumor morphology and worse outcome but does not improve prognostication beyond standard tumor budding assessment. TB-distance may still be useful as a visual aid in routine pathology and a quantifiable spatial feature for computational pathology.