Extranodal extension in lung adenocarcinoma: pathological insights and its implication as a histological marker of clinical aggressiveness.

BACKGROUND

Extranodal extension (ENE) is a recognized adverse prognostic factor in several malignancies, but its pathological basis and clinical significance in lung adenocarcinoma (LUAD) remain poorly understood.

METHODS

We retrospectively analyzed 105 patients with N1/N2 LUAD who underwent anatomical resection between 2016 and 2020. AI-assisted image analysis quantified tumor-infiltrating lymphocytes (CD8 + , FoxP3 + ), tumor-associated macrophages (CD204 + ), and cancer-associated fibroblasts (CAFs; podoplanin + ) and measured areas of cancer cells and fibrous stroma. In vitro, the effect of CAF quantity on A549 cell invasion was evaluated. Prognostic relevance of ENE was assessed using multivariate and cumulative incidence analyses.

RESULTS

While primary tumors showed no significant differences in immune or stromal composition, ENE-positive metastatic nodes exhibited a markedly larger fibrous stroma area than ENE-negative nodes (14.2 vs. 4.0 mm², p < 0.001). In vitro, the invasion distance of A549 cells increased when cocultured with higher numbers of CAFs. Clinically, ENE independently predicted poorer overall survival (p = 0.04) and was associated with a higher incidence of distant metastasis in both multivariate (p = 0.03) and cumulative incidence analyses (p = 0.02).

CONCLUSIONS

ENE represents a pathological prognostic factor characterized by abundant fibrous stroma. It independently predicts distant metastasis and may warrant consideration as a qualitative parameter in N classification for lung adenocarcinoma.