Histopathologic regression in lymph nodes predicts occult metastasis in ypT0 colorectal cancers after neoadjuvant...

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.