Significance of mucin-suspended tumor bud-like structures in colorectal cancer.

Tumor budding (TB) is an independent predictor of adverse prognosis in colorectal cancer (CRC), defined as clusters of fewer than 5 tumor cells at the invasive margin of cancer. According to the international consensus criteria (ITBCC), TB should be evaluated from the non-mucinous regions. However, some tumors also contain tumor bud-like structures within extracellular mucin pools, and the prognostic impact of these structures remains unclear. To assess this, we defined a modified tumor budding variable (TB-Muc), representing the highest number of tumor buds/bud-like structures observed in a hotspot (0.785 mm2) at the invasive margin, including extracellular mucin regions. We analyzed the prognostic significance of TB (ITBCC criteria) and TB-Muc in two CRC cohorts (N=1,876). TB-ITBCC was associated with advanced stage and lymphovascular invasion (p<0.001) but also with shorter cancer-specific survival independent of other prognostic factors (Cohort 1: HR for high vs. low 1.99, 95% CI 1.32-3.01, ptrend=0.0007; Cohort 2: HR 1.35, 95% CI 0.98-1.85, ptrend=0.037). TB-Muc had a comparable independent association with shorter cancer-specific survival (Cohort 1: HR for high vs. low 1.77, 95% CI 1.18-2.65, ptrend=0.006; Cohort 2: HR 1.39, 95% CI 1.02-1.89, ptrend=0.019). Our results indicate that tumor bud-like structures in mucin do not provide additional prognostic value and should not be included in TB evaluation.