Non-metastatic para-aortic lymph node remodeling as a predictor of outcome in locally advanced cervical cancer.

Abstract

Treatment of Locally Advanced Cervical Cancer (LACC) is guided notably by the European Society of Gynaecological Oncology (ESGO) guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histological assessment of non-metastatic para-aortic lymph node (PAoLN) provides prognostic value in LACC. Primary tumor and PAoLNs from 137 non-metastatic LACC patients were stratified by pre-therapeutic 18F-FDG PET/CT into pelvic PET-positive (pPET+, N= 72) and negative (pPET-, N= 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils (CD66b+, neutrophil extracellular traps: NETs) and high-endothelial venules (HEVs). Associations with progression-free survival (PFS) were examined via univariate and multivariate analyses after a median follow-up of 55.4 months. Primary tumor profile was not associated with outcome, whereas PAoLN features were strongly predictive. In pPET- patients, higher NETs were associated with shorter PFS (p=0.015; HR=2.768), while elevated CD4/CD8 ratio improved outcomes (p=0.047, HR=0.497). In pPET+ patients, shorter PFS was linked to FOXP3+ (p=0.04, HR=1.918) and proliferating FOXP3+ cells (p=0.018, HR=1.668) density. Across the full cohort, abundant germinal centers (p=0.0355, HR=0.273) and elevated CD4/CD8 ratio (p=0.001, HR=0.490) independently correlated with lower recurrence risk. Internal validation was conducted through a bootstrap resampling method. Combinatorial analyses revealed distinct predictive signatures according to pPET status: higher NETs, fewer germinal centers and FIGO-IIA1-IIIB status predicted relapse in pPET- patients. Integrating pPET status with PAoLN histological analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.