Stromal VEGF-C expression predicts nodal metastasis: implications for axillary surgery de-escalation in breast cancer

Accurate preoperative prediction of lymph node metastasis (LNM) is critical for de-escalating breast cancer surgery, sparing node-negative patients the morbidity of sentinel lymph node biopsy while ensuring appropriate staging for those at risk. Yet reliable molecular predictors of LNM remain lacking. VEGF-C, a key driver of lymphangiogenesis, is expressed in both cancer cell and stromal compartments, but its clinical utility is unclear. In a prospectively enrolled cohort, we assessed stromal and cancer cell VEGF-C expression by immunohistochemistry using both manual scoring and a novel automated image analysis script enabling objective, reproducible quantification of stromal versus epithelial VEGF-C fractions at scale. Stromal VEGF-C was independently associated with LNM after adjustment for established predictors (P = 0.004), with prediction models reaching AUCs of up to 0.784. Cancer cell VEGF-C added no predictive value. Critically, stromal VEGF-C showed potential to replace vascular invasion, which is a strong but preoperatively inaccessible predictor in LNM prediction models. Stromal VEGF-C assessment in preoperative biopsies could therefore enable more precise nodal staging, supporting informed surgical decision-making and the identification of patients who may safely avoid unnecessary axillary intervention.