Whole-Slide ECM Imaging Reveals Dense Fibrous Matrix as a High-Risk Factor for Recurrence in Stage II Colon Cancer

Abstract

Introduction: The extracellular matrix (ECM) supports tumor progression by influencing tumor cell migration and invasion. This study examines the link between peritumoral ECM morphology and five-year recurrence risk in TNM Stage II colon cancer, using quantitative whole-slide ECM imaging. We hypothesize that loose ECM regions are associated with increased recurrence risk due to enhanced tumor budding (TB) or poorly differentiated clusters (PDC). Methods: In a case-control study of 100 TNM Stage II colon cancer patients (25 with recurrence and 75 controls matched by lymph node sampling and tumor extent), Picrosirius red-stained sections were imaged to quantify ten ECM parameters across 798 regions of interest (ROIs). Conditional logistic regression assessed associations between ECM morphologies, TB, PDCs, and recurrence. Results: Unsupervised clustering identified three ECM morphologies: dense fibrous, loose sparse, and complex tortuous. Dense fibrous ECM correlated strongly with recurrence (aOR 9.43, 95% CI 3.29-29.30, p < 0.001), while loose sparse and complex tortuous ECMs were associated with reduced recurrence risk (aOR 0.33, 95% CI 0.11-0.91, p = 0.040, and aOR 0.14, 95% CI 0.02-0.53, p = 0.012, respectively). TB was highest in loose sparse ECM (mean 9.3), and PDCs were highest in dense fibrous ECM (mean 5.5). Discussion: Our findings suggest that ECM morphology, particularly dense fibrous ECM, predicts recurrence in Stage II colon cancer, highlighting ECM profiling as a promising tool for patient stratification beyond traditional staging.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

* https://github.com/cjravensbergen/MORTEX