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Histiocytosis or histiocytic disorders are characterized by abnormal function and accumulation or differentiation of specific cells, thought to be derived from dendritic cells (DCs) or the monocyte–macrophage lineage.1 Among this group of diseases, Langerhans cell histiocytosis (LCH) is the most common and is characterized by an activation of the MAPK-ERK pathway, driven by various molecular abnormalities in this pathway, particularly the canonical BRAFV600E mutation in about half of LCH lesions.2,3 Importantly, the cell-specific gene expression signature in Langerin (CD207)-positive cells within specific lesions has shown that LCH cells are more consistent with immature myeloid dendritic cell precursors than with Langerhans cells.4

LCH clinical manifestations range from mild, with a single organ involvement, to disseminated life-threatening presentations. Depending on the sites involved and severity, the entity now referred to as LCH has been previously defined as eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease. A more recent and simplified classification categorizes LCH based on single-organ or multisystem involvement.2 The systemic presentations of the disease are usually associated with a worse prognosis, particularly when the so-called risk organs (i.e., liver, spleen, and hematopoietic system) are involved. This severe form of LCH is encountered mainly in young children and more rarely in older patients.2,5

Lung involvement in LCH may occur less commonly as a part of a multisystemic disease, or most frequently as a single, primary involved organ. In this latter instance, the disease is usually called pulmonary LCH (PLCH).6 PLCH belongs to the spectrum of diffuse cystic lung diseases.7 It is characterized by the infiltration and destruction of bronchiolar walls by specialized dendritic cells organized into granulomas.6 However, lung interstitium and pulmonary vasculature may also be involved by the pathologic process to varying extents, resulting in diverse phenotypes. Although PLCH is classically considered as a distinct entity in which smoking habit plays a role, the discovery of MAPK-ERK mutations in this group of patients suggests a biologic similarity with other subtypes of LCH.8


LCH occurs sporadically, although rare familial cases and pairs of homozygous twins have been reported. The exact incidence and prevalence of PLCH are unknown. Early studies with a confirmed histologic diagnosis highlighted the rarity of the disease, which accounted for 3% to 5% of adult patients with diffuse infiltrative lung diseases.6 However, these reports most probably underestimated the true prevalence of PLCH. Indeed, with the wide use of chest high-resolution computed tomography (HRCT) in the routine evaluation of patients, increased numbers of PLCH cases were identified; lung biopsy is not systematically performed, and some patients exhibited no symptoms or experienced spontaneous remission.6 Occupational or geographic predisposition has not been reported. The most striking epidemiologic feature of PLCH is that it occurs almost exclusively in smokers or ex-smokers (>90% of cases).6 The role of smoking in triggering PLCH is ...

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