Spectrum of primary pulmonary lymphoepithelial carcinoma: from morphology to prognostic features

Primary pulmonary lymphoepithelial carcinoma (PPLEC) is a rare Epstein–Barr virus (EBV)-associated subtype of lung cancer classified under pulmonary squamous cell carcinoma (PSCC) in the fifth WHO classification of thoracic tumors. However, its clinicopathological features remain poorly defined. This study compared the histomorphological characteristics and prognostic outcomes of PPLEC and conventional non-keratinizing PSCC, a morphologically mimicking tumor entity. We retrospectively analyzed 103 Epstein-Barr virus-encoded small RNA (EBER)-positive PPLEC cases and 86 PSCC cases diagnosed at Shanghai Pulmonary Hospital from October 2014 to August 2023. Based on tumor morphology and tumor-infiltrating lymphocyte (TIL) density, lesions were categorized as stromal lymphocyte-rich or lymphocyte-poor subtypes. Clinicopathological features, immunohistochemistry, molecular profiles, and survival outcomes were evaluated. Compared with patients with PSCC, PPLEC cases presented a higher female proportion (37.9% vs. 7.0%, P < 0.001) and more peripheral lesions (86.4% vs. 34.9%, P < 0.001). Patients with PPLEC exhibited significantly prolonged overall survival (OS) relative to those with PSCC (89.2 vs. 52.7 months, P = 0.003). Univariate analysis revealed that PPLEC patients with tumor diameter > 3 cm, lymph node metastasis, advanced clinical stage, or spread through air spaces (STAS) exhibited shorter OS ( P = 0.004, 0.026, 0.002, and P < 0.001, respectively). The mean OS was significantly longer in patients with stromal lymphocyte-rich type PPLEC than in those with lymphocyte-poor PPLEC (103.2 vs. 82.9 months, P = 0.044). Multivariate Cox regression analysis identified clinical stage as an independent adverse prognostic factor ( P = 0.002). Among patients with stage I–II PPLEC, TIL density represented an independent prognostic factor for OS (HR = 0.42, 95% CI:0.23–0.78, P = 0.002). PPLEC exhibits a continuous histological spectrum, in which the stromal lymphocyte-rich subtype is associated with a more favorable prognosis. TIL density serves as a reliable prognostic biomarker in early-stage disease. For patients with tumors resembling non-keratinizing pulmonary squamous cell carcinoma, EBER in situ hybridization testing is useful for improving diagnostic accuracy and guiding individualized clinical management.