MMR Status Modulates the Predictive Value of Lymphatic Invasion for Lymph Node Metastasis in Gastrointestinal Cancers

Lymph node metastasis (LNM) is a key factor influencing treatment decisions and prognosis in patients with gastric cancer. Lymphatic invasion (LI) is an important pathological predictor of LNM and a core component of the eCURA risk scoring system after endoscopic submucosal dissection (ESD) for early gastric cancer. However, whether LI has the same predictive value for LNM across different mismatch repair (MMR) statuses remains unclear. Compared with proficient mismatch repair (pMMR) gastric cancer, deficient mismatch repair (dMMR) gastric cancer has distinct molecular pathological features and an immune-enriched tumor microenvironment. In early gastric cancer, if LI is associated with a lower LNM risk in dMMR tumors than in pMMR tumors, existing LI-based eCURA risk assessment may overestimate LNM risk in patients with dMMR early gastric cancer and consequently affect decisions regarding additional surgery after ESD. Therefore, this study aims to systematically evaluate the association between MMR status, LI, and LNM using multi-center cohorts of patients with GC who underwent upfront gastrectomy or additional gastrectomy following ESD, and to explore the potential clinical value of incorporating MMR status into eCURA-based risk stratification for early GC. Furthermore, an independent colorectal cancer surgical cohort will be included to investigate whether these associations are consistent across different gastrointestinal malignancies.

Inclusion Criteria: 1. Gastric cancer upfront surgery cohort * Patients who underwent radical surgery for gastric cancer. * Patients who did not receive neoadjuvant chemotherapy, radiotherapy, immunotherapy, or other antitumor treatments that may affect the pathological assessment of the primary tumor or lymph node metastasis before surgery. * Patients with pathologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma after surgery, including Siewert type II and III tumors only. * Patients with definite pathological assessment of lymphatic invasion and regional lymph node status. * Patients with available and definite MMR status. 2. Gastric cancer ESD cohort * Patients who underwent ESD for gastric cancer. * Patients with pathologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma after ESD, including Siewert type II and III tumors only. * Patients with complete post-ESD pathological information, including histological type, depth of invasion, tumor size, ulcerative findings, lymphatic invasion status, venous invasion status, horizontal margin status, and vertical margin status. * Patients with available and definite MMR status. 3. Colorectal cancer upfront surgery cohort * Patients who underwent radical surgery for colorectal cancer. * Patients who did not receive neoadjuvant chemotherapy, radiotherapy, immunotherapy, or other anti-tumor treatments that may affect the pathological assessment of the primary tumor or lymph node metastasis before surgery. * Patients with pathologically confirmed colorectal adenocarcinoma. * Patients with definite pathological assessment of lymphatic invasion and regional lymph node status. * Patients with available and definite MMR status. Exclusion Criteria: 1. Gastric cancer upfront surgery cohort * Patients with other pathological types, such as gastric squamous cell carcinoma or neuroendocrine carcinoma. * Patients who received neoadjuvant treatment before surgery, including chemotherapy, radiotherapy, immunotherapy, targeted therapy, or other systemic antitumor treatments. * Patients with missing postoperative pathological information, resulting in inability to determine lymphatic invasion or regional lymph node metastasis status. * Patients with missing or indeterminate MMR status. * Patients with concurrent malignancies that may interfere with the determination of the origin of lymph node metastasis. 2. Gastric cancer ESD cohort * Patients with other pathological types, such as gastric squamous cell carcinoma or neuroendocrine carcinoma. * Patients with missing post-ESD pathological information that precludes eCURA classification, eCURA risk score calculation, or assessment of lymphatic invasion status. * Patients with missing or indeterminate MMR status. 3. Colorectal cancer upfront surgery cohort * Patients with other pathological types, such as neuroendocrine carcinoma. * Patients who received neoadjuvant treatment before surgery, including chemotherapy, radiotherapy, immunotherapy, targeted therapy, or other systemic anti-tumor treatments. * Patients with missing postoperative pathological information, resulting in inability to determine lymphatic invasion or regional lymph node metastasis status. * Patients with missing or indeterminate MMR status. * Patients with concurrent malignancies that may interfere with the determination of the origin of lymph node metastasis.