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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.

Abstract：

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.

journal_name

Histopathology

journal_title

Histopathology

authors

Kamionek M,Ahmadi Moghaddam P,Sakhdari A,Kovach AE,Welch M,Meng X,Dresser K,Tomaszewicz K,Cosar EF,Mark EJ,Fraire AE,Hutchinson L

doi

10.1111/his.12955

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

499-509

issue

eissn

0309-0167

issn

1365-2559

journal_volume

pub_type

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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.