Nonmetastatic Para-aortic Lymph Node Remodeling as a Predictor of Outcome in Locally Advanced Cervical Cancer

Treatment of locally advanced cervical cancer (LACC) is guided notably by the European Society of Gynaecological Oncology guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histologic assessment of nonmetastatic para-aortic lymph nodes (PAoLN) provides prognostic value in LACC.

Primary tumor and PAoLNs from 137 patients with nonmetastatic LACC were stratified by pretherapeutic 18F-2'-deoxy-2'-fluorodeoxyglucose PET/CT into pelvic PET-positive (pPET+, n = 72) and pelvic PET-negative (pPET-, n = 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils [CD66b+, neutrophil extracellular traps (NET)], and high-endothelial venules (HEV). Associations with progression-free survival (PFS) were examined via uni- and multivariate analyses after a median follow-up of 55.4 months.

The 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; hazard ratio (HR) = 2.768], whereas an 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+ cell (P = 0.018, HR = 1.668) density. Across the full cohort, abundant germinal centers (P = 0.0355, HR = 0.273) and an 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 International Federation of Gynaecology and Obstetrics IIA1 to IIIB status predicted relapse in pPET- patients.

Integrating pPET status with PAoLN histologic analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.