Histopathologic regression in lymph nodes predicts occult metastasis in ypT0 colorectal cancers after neoadjuvant therapy: a retrospective cohort study.

In locally advanced colorectal cancer (LACRC), neoadjuvant therapy (NT) followed by total mesorectal or complete mesocolic excision is standard. Although a pathological complete response at the primary site (ypT0) predicts excellent survival, this benefit is offset when residual nodal metastasis (ypT0N⁺) is present. Reliable predictors of ypT0N⁺ are lacking. We retrospectively reviewed LACRC patients (2009-2024) who received NT and achieved ypT0 after curative surgery. Clinicopathologic variables were analyzed by uni- and multivariable logistic regression. A lymph node (LN) showing fibrosis, necrosis, acellular mucin, or foamy-cell reaction without viable carcinoma was classified as a regressed LN (RLN). An external ypT1-4 cohort treated during 2022-2024 served for validation. Among 503 ypT0 patients, 29 (5.8%) were ypT0N⁺. RLN-positivity occurred in 38% of ypT0N⁺ versus 10% of ypT0N0 cases (p < 0.001). On multivariable analysis, RLN-positivity was the sole independent risk factor for ypT0N⁺ (OR 4.11, 95% CI 1.71-9.52, p = 0.001). In the validation cohort (n = 615), RLNs remained enriched in ypN⁺ patients (21% vs 13%, p = 0.001), corroborating the association. RLN-positivity is a robust histologic marker of occult nodal metastasis in ypT0 LACRC. ypT0N0 should be diagnosed cautiously when RLNs are present, and such patients may require intensified adjuvant therapy and surveillance.