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.
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.
Authors: Huan Liu; Claudia Jakubzick; Andrew R Osterburg; Rebecca L Nelson; Nishant Gupta; Francis X McCormack; Michael T Borchers Journal: Am J Respir Cell Mol Biol Date: 2017-10 Impact factor: 6.914
Authors: Huan Liu; Andrew R Osterburg; Jennifer Flury; Zulma Swank; Dennis W McGraw; Nishant Gupta; Kathryn A Wikenheiser-Brokamp; Ashish Kumar; Abdellatif Tazi; Yoshikazu Inoue; Masaki Hirose; Francis X McCormack; Michael T Borchers Journal: JCI Insight Date: 2020-02-27
Authors: Xiaoqin Zhu; Sarah Jamshed; Jian Zou; Azniv Azar; Xiuling Meng; Venu Bathini; Karen Dresser; Cara Strock; Bhargavi Yalamarti; Michelle Yang; Keith Tomaszewicz; George Tjionas; Mark C Mochel; Lloyd Hutchinson; Jacob R Bledsoe Journal: Mod Pathol Date: 2021-01-22 Impact factor: 8.209