High prevalence of loss of Claudin‐18 expression in invasive non‐mucinous lung adenocarcinoma: Potential diagnostic implications in routine practice

Aims: Accurate diagnosis of lung adenocarcinoma (LUAD), particularly in small biopsy specimens, can be challenging due to limited tissue availability and the presence of histological mimickers. Claudin-18 (Cldn18), a tight junction protein with a lung-specific isoform (Cldn18.1), is normally expressed in alveolar epithelium and is implicated in maintaining alveolar integrity. Loss of Cldn18 has been linked to LUAD development through dysregulated YAP signalling. This study evaluated Cldn18 expression across lung cancer subtypes, with particular focus on LUAD. Methods and results: Cldn18 immunohistochemical expression was retrospectively assessed in 391 lung resection specimens and 53 small biopsy samples. Normal alveoli and reactive pneumocytes consistently expressed Cldn18, whereas LUADs, especially non-mucinous LUADs (NM-LUADs), typically showed marked loss. Complete absence of Cldn18 was observed in 83% of NM-LUAD resections and 84.8% of NM-LUAD biopsies. ROC analysis demonstrated excellent diagnostic accuracy (AUC 0.992), with sensitivity of 98.4% and specificity of 100%. Lepidic NM-LUAD components, a frequent diagnostic pitfall especially in small specimens, showed low expression in most cases (>50% of tumour cells in 24/26). Similarly, 6/7 atypical adenomatous hyperplasia (AAH) cases exhibited low expression, while all reactive pneumocyte proliferations retained staining. By contrast, mucinous LUADs (M-LUADs) preserved Cldn18 expression in 35/54 cases, providing a clear distinction from NM-LUADs with mucin production. Conclusions: Cldn18 loss is a promising diagnostic biomarker for NM-LUAD. Complete loss of Cldn18 expression could serve as an ancillary tool for distinguishing malignant lesions from NM-LUAD mimickers and for differentiating NM-LUADs with mucin production from true M-LUADs, particularly in small or challenging biopsies.