Context-Dependent Prognostic Role of Neutrophils and Mast Cells in Primary Colorectal Cancer and Liver Metastases

Abstract

BACKGROUNDColorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Liver metastases (LM) are a major prognostic factor affecting survival and treatment outcomes. Distinguishing between synchronous and metachronous metastases is clinically important due to differences in tumor biology, immune contexture, and prognosis. Polymorphonuclear neutrophils (PMNs) and mast cells (MCs) are innate immune effectors that influence CRC progression and metastasis. However, their distribution across primary tumors (pCRC), nontumor mucosa (NM), and liver metastases (LM), and prognostic relevance remain incompletely understood.AIMTo evaluate distribution and prognostic value of PMNs and MCs in NM, pCRC, and LM in synchronous and metachronous CRC.METHODSThis exploratory retrospective cohort study included patients undergoing resection of pCRC with NM and synchronous LM (stage IV, n = 55) or metachronous LM (stage I-III, n = 44). CD66b+ PMNs and CD117+ MCs were assessed using immunohistochemistry, whole-slide imaging, and QuPath-based quantification across NM, tumor center (TC), inner (IM) and outer margins (OM), and peritumor zone (PT) of pCRC and LM. Cell densities were compared by site, region, and timing of metastatic presentation, and associated with disease-free survival (DFS).RESULTSPMNs were enriched in pCRC compared to NM, whereas MCs predominated in NM. Greater densities of PMNs and MCs were found in LM and pCRC, respectively. High PMNs in OM (HR=2.40, 95%CI: 1.14-5.04, p=0.021) and PT (HR=2.58, 95%CI: 1.22-5.46, p=0.013) of synchronous LM and OM of pCRC in stage I-III (HR=2.59, 95%CI: 1.11-6.02, p=0.027) correlated with shorter DFS, whereas high PMNs in TC of metachronous LM predicted longer DFS (HR=0.48, 95% CI: 0.24-0.99, p=0.048). High MCs densities in TC of pCRC in stage I-III predicted shorter DFS (HR=2.34, 95%CI: 1.05-5.23, p=0.038).CONCLUSIONPMNs density increased from NM to LM, while MCs decreased. MCs showed protumor prognostic associations in pCRC; PMNs were protumor in stage I-III pCRC and synchronous LM, but antitumor in metachronous LM.