The prognostic effect of perineural invasion in esophageal squamous cell carcinoma

Abstract

Background: Perineural invasion (PNI) is correlated with adverse survival in several malignancies, but its significance in esophageal squamous cell carcinoma (ESCC) remains to be clearly defined. The objective of this study was to determine the association between PNI status and clinical outcomes.

Methods: We retrospectively evaluated the PNI of 433 patients with ESCC treated with surgery between 2000 and 2007 at a single academic center. The resulting data were analyzed using Spearman's rank correlation, the Kaplan-Meier method, Cox proportional hazards regression modeling and Harrell's concordance index (C-index).

Results: PNI was identified in 209 of the 433 (47.7%) cases of ESCC. The correlation analysis demonstrated that PNI in ESCC was significantly correlated with tumor differentiation, infiltration depth, pN classification and stage (P < 0.05). The five-year overall survival rate was 0.570 for PNI-negative tumors versus 0.326 for PNI-positive tumors. Patients with PNI-negative tumors exhibited a 1.7-fold increase in five-year recurrence-free survival compared with patients with PNI-positive tumors (0.531 v 0.305, respectively; P < 0.0001). In the subset of patients with node-negative disease, PNI was evaluated as a prognostic predictor as well (P < 0.05). In the multivariate analysis, PNI was an independent prognostic factor for overall survival (P = 0.027). The C-index estimate for the combined model (PNI, gender and pN status) was a significant improvement on the C-index estimate of the clinicopathologic model alone (0.739 v 0.706, respectively).

Conclusions: PNI can function as an independent prognostic factor of outcomes in ESCC patients, and the PNI status in primary ESCC specimens should be considered for therapy stratification.

Figure 1

The status of perineural invasion (PNI) in ESCC specimens. Tumor cells located within any of the endoneurium (A), perineurium (B) and epineurium (C) of the peripheral nerve sheath are clear examples of PNI. When tumor cells are not located inside of the nerve sheath but are in close proximity to the nerve in the perineural environment, at least 33% of the circumference of the nerve should be surrounded by tumor cells to diagnose PNI (D); anything less than 33% represents focal abutment and not invasion (E). When tumor cells are not in close proximity to the nerve in the perineural environment (F), it represents negative finding (hematoxylin-eosin staining, ×100).

Figure 2

The association between perineural invasion and ESCC patients’ survival (log-rank test). Kaplan-Meier survival analysis of perineural invasion for overall survival (A) and recurrence-free survival (B) in ESCC patients.

Figure 3

Univariate survival analysis with regard to perineural invasion in the subset of ESCC patients with node-negative disease. The presence of perineural invasion was identified as a prognostic predictor of overall survival (A) and recurrence-free survival (B) in ESCC patients with node-negative disease.