Systemic immune-inflammation indices and MSI-H/dMMR status in colorectal cancer: Published evidence synthesis with exploratory local clinical and pathological corroboration

Abstract

Background: Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) colorectal cancer (CRC) is a biologically distinct subtype with important clinical implications. While tissue-based assays remain the standard, accessible preoperative surrogate markers are of interest. Systemic inflammatory indices, including the systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR), have been explored, but their relationship with MSI-H/dMMR status remains unclear.

Objective: To evaluate the association between systemic inflammatory indices and MSI-H/dMMR status using published evidence, local clinical data and pathological corroboration.

Methods: This study included three components: (1) evidence synthesis of published cohorts comparing inflammatory indices between MSI-H/dMMR and MSS/pMMR CRC; (2) a retrospective cohort of 28 patients (20 MSS and eight MSI-H) assessing peripheral blood profiles and exploratory associations; and (3) immunohistochemical quantification of CD8 and myeloperoxidase (MPO) using a Python/OpenCV workflow.

Results: Six studies (n = 1598) were included in the NLR synthesis. The pooled random-effects standardised mean difference was 0.93 (95% confidence interval [CI] 0.016–1.852), suggesting higher NLR in MSI-H/dMMR cases, although heterogeneity was high (I² = 97.8%). Excluding one influential study reduced the effect to 0.34 (95% CI −0.00 to 0.68). One study of SII suggested a modest increase in MSI-H/dMMR cases. In the local cohort, lymphocyte count was higher in MSI-H cases (p = .009), whereas SII and NLR were lower but not significant. Receiver operating characteristic analysis showed modest discrimination (SII area under the curve [AUC] = 0.675; NLR AUC = 0.656). Pathological quantification showed increased CD8 and reduced MPO/CD8 ratio in MSI-H tumours.

Conclusions: MSI-H/dMMR CRC exhibits a distinct but context-dependent immune-inflammatory phenotype. Systemic indices show heterogeneous patterns, while tissue findings indicate a lymphocyte-enriched microenvironment. These markers may provide supportive immune context, but further validation is required.

Trial registration: PROSPERO CRD420261323742 (https://www.crd.york.ac.uk/PROSPERO/view/CRD420261323742).

Keywords

colorectal cancer / deficient mismatch repair / evidence synthesis / immunohistochemistry / microsatellite instability / neutrophil-to-lymphocyte ratio / systemic immune-inflammation index

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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.