Perineural invasion affects the risk and pattern of recurrence in non-small cell lung cancer

Abstract OBJECTIVES We evaluated the impact of perineural invasion on recurrence risk and patterns in patients with non-small-cell lung cancer. METHODS We retrospectively analyzed 5,545 patients who underwent curative resection for pathologic stage I–III non-small-cell lung cancer between 2009 and 2021. Perineural invasion was defined as the presence of tumour cells within nerve sheath layers or tumour foci involving ≥33% of the nerve’s circumference. After stratifying patients by perineural invasion status, we compared recurrence-free survival and recurrence patterns. RESULTS Perineural invasion was identified in 290 patients (5.3%), with prevalence increasing by stage (1.8%, 11.6%, and 18.7% in stage I, II, and III, respectively). The perineural invasion (+) group included higher proportions of males and smokers, had lower pulmonary function, higher SUVmax, more advanced pathological stage, and increased prevalence of squamous cell carcinoma and other pathologic invasiveness markers. The cumulative incidence of recurrence was significantly higher in the presence of perineural invasion (5-year cumulative incidence: 42.4% in the perineural invasion (+) group vs 16.5% in the perineural invasion (–) group; Gray’s test, p < 0.001). Stage-stratified multivariable analysis demonstrated that perineural invasion increased recurrence risk in stages I-II (p < 0.001 and p = 0.021, respectively), but not in stage III (p = 0.245). This trend was consistent in the interaction analysis (p < 0.001). In the recurrence pattern analysis, extrathoracic recurrence was more frequent when perineural invasion was present (p = 0.002). CONCLUSIONS Perineural invasion is associated with an increased risk of recurrence in NSCLC, particularly in early-stage disease. When perineural invasion is present, extrathoracic recurrence is observed more frequently.