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Introduction: The long-term outcome of adult pulmonary Langerhans cell histiocytosis (PLCH) is unclear and an association with malignancy is strongly suspected. Aims and Objectives: Our objectives were to determine the overall survival of adult PLCH patients and the incidence of chronic respiratory failure (CRF), pulmonary hypertension (PH), and malignant disorders during follow-up. Methods: All PLCH patients newly diagnosed at adulthood at the French National Reference Centre for Histiocytoses between January 2004 and April 2018 and prospectively registered were included. Results: Two hundred and six patients (39 ± 13 years, 60% females, 95% current smokers) were followed for a median time of 5.1 years; IQR 3.2; 7.6. Twelve patients died during the study. The main cause of death was malignancy (42%, mostly lung cancer). The estimated rates of survival at 5 and 10 years after PLCH diagnosis were 94% (95%CI 90; 98) and 93% (95%CI 89; 97), respectively. The 5 year cumulative incidence of CRF and PH was 6.3% (95%CI 3.4; 10.4) and 5.5% (95%CI 2.8; 9.5), respectively, with no further events after 5 years. Twenty-seven malignancies (11 lung cancer, 41%) were observed in 23 patients, before (n=11), at the time (n=6), or after PLCH diagnosis (n=10, within a median time of 4.1 years; IQR 3.1; 5.0). The incidence of lung cancer was significantly higher than that expected using age- and sex-specific rates from the French population (SIR=16.7, 95%CI 7.3; 38.1). Conclusions: Our findings provide important clues for the management of adult PLCH patients. Further studies are needed to identify risk factors for CRF and clarify the underlying mechanisms of cancer excess in PLCH.

Langerhans cell histiocytosis (LCH) is currently considered a rare neoplastic disease with an inflammatory component, driven by genomic alterations in the mitogen-activating protein kinase (MAPK) pathway, including BRAFV600E, MAP2K1 mutations and BRAF deletions [1, 2]. Lung involvement is frequently observed in adult LCH patients, almost exclusively in young smokers of both sexes [3]. The aetiology of LCH, including pulmonary LCH (PLCH), remains unknown. A viral triggering factor of LCH has long been suspected, but the results of studies are inconclusive [4, 5]., Compared to control lung tissues from smokers, MCPyV DNA is rarely detected in PLCH lesions and is not associated with alterations of the MAPK pathway. A viral trigger in PLCH pathogenesis remains elusive. https://bit.ly/2xKmkIo

Background: The prevalence of neuropsychiatric symptoms and substance abuse disorders, in adult patients with pulmonary Langerhans cell histiocytosis (PLCH) has not been explored. Objectives: The aim of this study was to examine the psychological healthcare burden faced by PLCH patients. Methods: All PLCH patients seen during one year completed the Hospital Anxiety and Depression scale (HAD), the Barratt Impulsiveness Scale, Version 10 (BIS-10) and the Cannabis Use Disorders Identification Test (CUDIT) questionnaires. Scores were used to determine the prevalence of psychological and substance abuse problems, and were associated with clinical assessment of the disease. The primary endpoint of the study was the proportion of patients having definite or doubtful anxious state (HAD-A scores of 11 or higher or between 8 and 10, respectively). Logistic regression models were used to quantify the strength of association of various disease-related parameters and the occurrence of anxiety, depression or impulsivity. Results: Sixty-eight patients were included. Definite anxious and depressive states were identified in 29% and 6% patients, respectively, and doubtful anxious and depressive states in 34% and 6%, respectively. Impulsive behaviour was detected in 13% of the cohort. Eleven patients (16%) consumed cannabis on a regular basis, and in 55% of them CUDIT scores suggested cannabis abuse or dependence. Increasing time from diagnosis and successful cessation of cigarette smoke exposure were associated with decreased risk of anxiety. Conclusions: Psychological abnormalities commonly co-exist in adult PLCH patients and should be considered while making their management decisions.

Background: The clinical significance of the BRAFV600E mutation in tissue lesions from patients with pulmonary Langerhans cell histiocytosis (PLCH) has not been evaluated. Objective: To search for an association between BRAFV600E mutation and PLCH presentation and outcome. Methods:BRAFV600E genotyping was performed in biopsies from 83 patients with PLCH (43 males, median age 36 years, 65 current smokers). The outcome was based on variations of lung function tests and the occurrence of a new pneumothorax during the study [1]. Cox models were used to estimate the strength of association of baseline characteristics on the hazard of PLCH progression. P-values ≤0.05 denoted statistical significance. Results: A BRAFV600E mutation was detected in 31(37%) cases. No difference was identified in PLCH presentation, including smoking status (p=0.42), pneumothorax (p=0.29), or lung function (p>0.05), according to BRAF status. Patients were followed for a median time of 5 years. Thirty-eight (46%) patients experienced lung progression. BRAF status was not associated with PLCH outcome (Figure). In multivariable analysis, airflow obstruction at diagnosis was associated with increased risk of lung progression (p=0.028). Conclusions:BRAFV600E mutation was not associated with clinical features or outcome in adult PLCH patients. Airflow obstruction at diagnosis was the main factor associated with the risk of lung progression overtime.

Background: Pneumothorax (PNO) is a salient complication of PLCH, which management is not standardized. The factors associated with PNO recurrence are poorly understood. Objectives: To determine PNO outcome after thoracic surgery and search for factors associated with the risk of recurrence. Methods: All PLCH patients ≥18 years with ≥1PNO between 11/2003 and 12/2015 of the database of the National Registry for histiocytoses and followed ≥6 months were retrospectively studied. Kaplan Meier method and univariate Cox models were used for statistical analyses. Results: Among the 43 patients included (39 smokers), 53% presented at least 1 PNO recurrence during a 49 months median time (53 additional episodes, 75% ipsilateral, all within 2 years). Thoracic surgery did not modify the risk of PNO recurrence, as compared to conservative treatment (p=0.96). However, the rate of recurrences was lower after thoracotomy (TCT), as compared to video-assisted thoracoscopy (VATS) (p=0.03). In the univariate analyses, lung function air trapping at diagnosis was associated with increased hazard of PNO recurrence (p=0.03). Patients whose LCH lesion harboured the BRAFV600E mutation had a lower rate of ipsilateral recurrences (p=0.019). When incorporating all ipsilateral recurrences, VATS was associated with increased hazard of subsequent recurrence (p=0.05). Conclusions: Surgery did not decrease the risk of PNO recurrence in PLCH. Thus, no particular treatment can be recommended for the first PNO in PLCH patients. In case of recurrence, TCT which appears more effective than VATS to prevent subsequent recurrence, should be privileged. The reduced risk of PNO recurrence associated with the presence of BRAFV600E mutation needs to be confirmed.