{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T22:30:33Z","timestamp":1768429833264,"version":"3.49.0"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,4,29]],"date-time":"2016-04-29T00:00:00Z","timestamp":1461888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Pulmonary Langerhans cell histiocytosis (<jats:styled-content style=\"fixed-case\">PLCH<\/jats:styled-content>) is an idiopathic cigarette smoking\u2010related disorder of the lung. Molecular changes in cellular or fibrotic stages of <jats:styled-content style=\"fixed-case\">PLCH<\/jats:styled-content> have not been investigated. We studied the prevalence of extracellular signal\u2010regulated kinase (<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>) pathway mutations in different <jats:styled-content style=\"fixed-case\">PLCH<\/jats:styled-content> stages and other non\u2010<jats:styled-content style=\"fixed-case\">PLCH<\/jats:styled-content> smoking\u2010related lung diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>The cohort included 28 <jats:styled-content style=\"fixed-case\">PLCH<\/jats:styled-content> with cellular (<jats:italic>n<\/jats:italic> = 10), mixed cellular\/fibrotic (<jats:italic>n<\/jats:italic> = 4) and fibrotic histology (<jats:italic>n<\/jats:italic> = 14). Seven cases had concurrent multi\u2010focal\/multi\u2010lobar tumours. Respiratory bronchiolitis interstitial lung disease (<jats:styled-content style=\"fixed-case\">RB<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">ILD<\/jats:styled-content>,<jats:italic> n<\/jats:italic> = 2), desquamative interstitial pneumonia (<jats:styled-content style=\"fixed-case\">DIP<\/jats:styled-content>,<jats:italic> n<\/jats:italic> = 4) and mixed <jats:styled-content style=\"fixed-case\">RB<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">ILD<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">DIP<\/jats:styled-content> (<jats:italic>n<\/jats:italic> = 2) were included for comparison. <jats:styled-content style=\"fixed-case\">BRAF<jats:sup>V<\/jats:sup><\/jats:styled-content><jats:sup>600E<\/jats:sup>immunohistochemistry, next\u2010generation sequencing (<jats:styled-content style=\"fixed-case\">NGS<\/jats:styled-content>) and peptide nucleic acid (<jats:styled-content style=\"fixed-case\">PNA<\/jats:styled-content>) clamp polymerase chain reaction (<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>) with high analytical sensitivity (&lt;0.1\u20130.2%) were used to analyse <jats:italic><jats:styled-content style=\"fixed-case\">RAS<\/jats:styled-content><\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content><\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content>2K1<\/jats:italic> genes. Of 26 cases with gene mutation data, <jats:styled-content style=\"fixed-case\"><jats:italic>BRAF<\/jats:italic><jats:sup>V<\/jats:sup><\/jats:styled-content><jats:sup>600E<\/jats:sup> was identified in eight of 12 (67%) cellular cases and in one of 14 (7%) fibrotic cases. <jats:italic><jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content>2K1<\/jats:italic> or <jats:italic><jats:styled-content style=\"fixed-case\">KRAS<\/jats:styled-content><\/jats:italic> mutations were observed in four of 14 (29%) fibrotic cases and three of the 12 (25%) cellular cases. Multi\u2010focal\/multi\u2010lobar specimens carried identical <jats:italic><jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content><\/jats:italic> (<jats:italic>n<\/jats:italic> = 5) or non\u2010hotspot <jats:italic><jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content>2K1<\/jats:italic> (<jats:italic>n<\/jats:italic> = 2) mutations. The other smoking\u2010related disorders were negative for mutations. Patients with cellular lesions or <jats:italic><jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content><\/jats:italic> mutation were significantly younger than patients with fibrotic or <jats:italic><jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content><\/jats:italic> wild\u2010type <jats:styled-content style=\"fixed-case\">PLCH<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The presence of identical but mutually exclusive <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> pathway mutations in multi\u2010focal <jats:styled-content style=\"fixed-case\">PLCH<\/jats:styled-content> 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\u2010specific pathogenicity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.12955","type":"journal-article","created":{"date-parts":[[2016,2,26]],"date-time":"2016-02-26T08:22:41Z","timestamp":1456474961000},"page":"499-509","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Mutually exclusive extracellular signal\u2010regulated kinase pathway mutations are present in different stages of multi\u2010focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease"],"prefix":"10.1111","volume":"69","author":[{"given":"Michal","family":"Kamionek","sequence":"first","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parnian","family":"Ahmadi Moghaddam","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Massachusetts Medical School Worcester MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Sakhdari","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Massachusetts Medical School Worcester MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra E","family":"Kovach","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Welch","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Massachusetts Medical School Worcester MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuling","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Massachusetts Medical School Worcester MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Dresser","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Massachusetts Medical School Worcester MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith","family":"Tomaszewicz","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Massachusetts Medical School Worcester MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ediz F","family":"Cosar","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Massachusetts Medical School Worcester MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene J","family":"Mark","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Armando 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