E-cadherin is a critical cell adhesion molecule with a tumor suppressive role. Reduced membranous E-cadherin expression is considered a central step in the progression and metastatic spread in human cancers. To study the prevalence and potential role of reduced E-cadherin expression in different lung cancer subtypes, E-cadherin expression was analyzed in more than 850 resected lung cancers by IHC in a tissue microarray format. A membranous E-cadherin staining was seen in 779 (96.9%) of the 804 interpretable tumor samples. A loss of E-cadherin expression was slightly more frequent in adenocarcinomas (ACs; 1.1%) than in squamous cell carcinomas (SCCs; 0.0%; p < 0.0001). Among the less common tumor entities, E-cadherin immunostaining was absent in 57.1% of 35 mesotheliomas, but retained in all cases of carcinoid (n = 52), large cell neuroendocrine carcinoma (n = 19), undifferentiated large cell carcinoma (n = 3), carcinosarcoma (n = 2), pleiomorphic carcinoma (n = 11), adenosquamous carcinoma (n = 8), mucoepidermoid carcinoma (n = 1), lymphoepithelial carcinoma (n = 1), and SMARCA4-deficient undifferentiated tumors (n = 1). Reduced E-cadherin immunostaining was significantly linked to advanced pT stage (p = 0.0265) and high grade (p = 0.0351) in ACs. Univariate outcome analysis revealed a significant association between E-cadherin expression and patient survival in all NSCLCs (p < 0.0001) and in ACs (p = 0.0133). It is concluded that loss of E-cadherin expression occurs in only a small subset of NSCLCs, that it is more frequent in ACs compared to SCCs and that reduced E-cadherin expression is linked to poor prognosis and unfavorable histopathological features in ACs. Should targeted therapy become available in the future, a small subset of pulmonary ACs and many mesotheliomas could be candidates for treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-45409-0.
