Low muscle density is associated with morbidity and systemic inflammation in colorectal cancer, independent of tumor factors

Background: Low skeletal muscle index (SMI) and skeletal muscle density (SMD) are associated with poor postoperative outcomes in colorectal cancer (CRC). However, standardized diagnostic thresholds remain undefined. Methods: In total, 927 patients with stage I-IV CRC were included. Preoperative computed tomography was used to determine body composition parameters. Optimal stratification was applied to identify the sex- and body mass index (BMI)-specific SMD and SMI cutoffs. SMD and SMI were analyzed as continuous variables relative to clinicopathologic features, systemic inflammatory markers, and sex-specific quartiles in survival analyses using Kaplan-Meier and Cox regression methods. Results: Optimal stratification did not yield reproducible cutoff values for SMI or SMD. In multivariable analysis, low SMD and SMI were associated with female sex, older age, and BMI, while tumor-related factors were not associated with either measure. Low SMD was associated with systemic inflammation, including elevated circulating CRP and IL6 levels, whereas low SMI showed only a nominal association with elevated IL6 levels after adjustment. Low SMD independently predicted poorer CSS (multivariable HR for lowest vs highest SMD 4.29, 95% CI 1.86-9.91, p=0.001), and OS (HR for lowest vs highest SMD, 3.42; 95% CI 1.62-7.25, p=0.003) in women but not in men, whereas SMI was not associated with survival. Conclusions: Low SMD is a sex-specific prognostic factor. Incorporating SMD assessment into preoperative risk stratification may enhance individualized management, particularly for female patients. Impact: Survival-based cutoff values for SMD or SMI in CRC could not be established. Moreover, preoperative body composition reflects patient-related factors rather than tumor-induced changes.