Perineural Invasion in Early-Stage Cervical Cancer: Marker of Aggressive Pathology and Increased Recurrence Risk

<b>Background:</b> Perineural invasion (PNI) is associated with aggressive tumor behavior in several malignancies, but its independent prognostic value in early-stage cervical cancer remains uncertain. We evaluated the clinical significance of PNI and explored molecular and immune features associated with PNI. <b>Methods:</b> We retrospectively analyzed 499 patients with FIGO 2009 stage IB-IIA cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy. Associations between PNI, clinicopathological variables, recurrence-free survival, and overall survival were assessed using Kaplan-Meier methods and Cox regression. An independent cohort of 286 cervical cancers from The Cancer Genome Atlas (TCGA) was analyzed to characterize PNI-associated transcriptomic patterns, pathway enrichment, immune cell composition, and microRNA profiles. <b>Results:</b> PNI was identified in 11.6% of cases and was associated with larger tumor size, deep stromal invasion, and lymphovascular space invasion. PNI was not an independent prognostic factor in the overall cohort; however, it was associated with increased recurrence risk in the subgroup without high-risk factors and not meeting Sedlis criteria, with a modest improvement in 5-year recurrence discrimination when incorporated into Sedlis-based models. In TCGA, PNI was associated with differential gene expression and enrichment of oncogenic and immune-related pathways, an increased estimated abundance of resting mast cells, and six differentially expressed microRNAs. <b>Conclusions:</b> In early-stage cervical cancer, PNI is strongly correlated with established adverse pathological features and shows a subgroup-specific association with recurrence in an otherwise low-risk postoperative population. The multi-omics findings are exploratory and support biological hypotheses regarding tumor-nerve-immune interactions; external validation is needed before PNI can be used to guide postoperative management.