Acellular mucin pools and neutrophil‐to‐lymphocyte ratio: unveiling hidden aggressiveness in pathological complete response after chemoradiotherapy for rectal cancer

Background Pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) does not eliminate tumor recurrence risk, with distant metastasis remaining a critical challenge. This study aimed to identify novel prognostic factors for risk stratification in pCR patients after nCRT. Methods We enrolled 149 LARC patients who achieved pCR between 2016 and 2020. Acellular mucin pools (AMP) were classified by the deepest tissue layer of AMP (A0: absent; A1: within the muscularis propria; A2: exceeding the muscularis propria). The primary endpoint was disease‐free survival (DFS); secondary endpoints included overall survival (OS) and recurrence patterns. Results After a median follow‐up of 75.3 months, the 5‐year OS and DFS rates were 95.3% and 89.9%, respectively. Among 15 recurrence events, all were distant metastases (80% pulmonary). AMP were present in 17.4% (26/149) of patients. Multivariate analysis identified AMP exceeding the muscularis propria (HR = 3.996, 95% CI: 1.073–14.660, P = 0.039), preoperative neutrophil‐to‐lymphocyte ratio (NLR) >4.4 (HR = 3.658, 95% CI: 1.304–10.263, P = 0.014) and tumour distance from the anal verge on pretreatment magnetic resonance imaging (MRI) (HR = 0.667, 95% CI: 0.481–0.925, P = 0.015) as independent predictors of distant metastasis‐free survival (DMFS). A nomogram integrating these factors showed robust discriminative performance for 1‐, 3‐, and 5‐year DMFS (AUC = 0.689, 0.815, 0.795). Meanwhile, AMP exceeding the muscularis propria (HR = 6.632, P = 0.010) and pretreatment MRI‐assessed tumour distance from the anal margin (HR = 0.614, P = 0.018) were independent predictors for pulmonary metastasis. Conclusions AMP exceeding the muscularis propria and high pretreatment NLR are complementary prognostic markers that refine risk stratification in pCR patients, enabling personalized surveillance and treatment strategies to improve outcomes.