Mutually exclusive extracellular signal-regulated kinase pathway mutations are present in different stages of multi-focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease

Aims Pulmonary Langerhans cell histiocytosis (PLCH) is an idiopathic cigarette smoking‐related disorder of the lung. Molecular changes in cellular or fibrotic stages of PLCH have not been investigated. We studied the prevalence of extracellular signal‐regulated kinase (ERK) pathway mutations in different PLCH stages and other non‐PLCH smoking‐related lung diseases. Methods and results The cohort included 28 PLCH with cellular (n = 10), mixed cellular/fibrotic (n = 4) and fibrotic histology (n = 14). Seven cases had concurrent multi‐focal/multi‐lobar tumours. Respiratory bronchiolitis interstitial lung disease (RB‐ILD, n = 2), desquamative interstitial pneumonia (DIP, n = 4) and mixed RB‐ILD/DIP (n = 2) were included for comparison. BRAFV600Eimmunohistochemistry, next‐generation sequencing (NGS) and peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) with high analytical sensitivity (