Nodal burden modifies the prognostic significance of perineural invasion in stage I-III gastric cancer.

BACKGROUND

Perineural invasion (PNI) is an established adverse prognostic factor in gastric cancer, but whether its prognostic effect varies with nodal burden and first metastatic site remains unclear.

METHODS

We retrospectively analyzed 12,898 patients with stage I-III gastric cancer who underwent curative-intent R0 gastrectomy at Fudan University Shanghai Cancer Center between 2000 and 2022. Multivariable Cox models with a pre-specified PNI-by-positive-node interaction estimated associations with overall survival (OS) and progression-free survival (PFS). First distant metastatic site was evaluated using Fine-Gray and Firth logistic site-contrast models. The PNI-nodal-burden association was assessed in an independent pathology cohort and the ACRG cohort.

RESULTS

Each additional positive lymph node attenuated the PNI-associated hazard ratio for OS (interaction HR, 0.976) and PFS (interaction HR, 0.977; both interaction P < 0.001). PNI was independently associated with poorer OS (HR, 1.38; 95% CI 1.20-1.59) and PFS (HR, 1.32; 95% CI 1.15-1.51) in N0-N1 disease, but the associations were attenuated in N2-N3 disease (OS: HR, 1.12; 95% CI 1.00-1.24; PFS: HR, 1.09; 95% CI 0.99-1.21). Among N0-N1 patients with pT3-pT4 disease and liver-only or peritoneal-only first metastasis, PNI was associated with peritoneal rather than hepatic dissemination (OR, 3.87; 95% CI 1.54-10.63).

CONCLUSIONS

The prognostic association of PNI was modified by nodal burden and was most evident in N0-N1 gastric cancer. These site-specific findings support prospective evaluation of PNI-informed, peritoneum-directed surveillance.