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

Histopathology. 2016 Sep;69(3):499-509. doi: 10.1111/his.12955. Epub 2016 Apr 29.


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. BRAF(V) (600E) immunohistochemistry, next-generation sequencing (NGS) and peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) with high analytical sensitivity (<0.1-0.2%) were used to analyse RAS, BRAF and MAP2K1 genes. Of 26 cases with gene mutation data, BRAF(V) (600E) was identified in eight of 12 (67%) cellular cases and in one of 14 (7%) fibrotic cases. MAP2K1 or KRAS mutations were observed in four of 14 (29%) fibrotic cases and three of the 12 (25%) cellular cases. Multi-focal/multi-lobar specimens carried identical BRAF (n = 5) or non-hotspot MAP2K1 (n = 2) mutations. The other smoking-related disorders were negative for mutations. Patients with cellular lesions or BRAF mutation were significantly younger than patients with fibrotic or BRAF wild-type PLCH.

Conclusion: The presence of identical but mutually exclusive ERK pathway mutations in multi-focal PLCH supports a neoplastic/clonal origin for this disease. Patient age and mutation type differed between cellular and fibrotic histology and may indicate a natural progression or a mutation-specific pathogenicity.

Keywords: ERK pathway; PLCH; clonal neoplasm; natural history; pathogenesis.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • DNA Mutational Analysis
  • Female
  • High-Throughput Nucleotide Sequencing
  • Histiocytosis, Langerhans-Cell / etiology
  • Histiocytosis, Langerhans-Cell / genetics*
  • Histiocytosis, Langerhans-Cell / pathology
  • Humans
  • Immunohistochemistry
  • Lung Diseases / etiology
  • Lung Diseases / genetics*
  • Lung Diseases / pathology
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Signaling System / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins B-raf / genetics
  • Real-Time Polymerase Chain Reaction
  • Smoking / adverse effects
  • Young Adult
  • ras Proteins / genetics


  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • ras Proteins