Pulmonary Langerhans cell histiocytosis - an update on pathogenesis and treatment.

PURPOSE OF REVIEW: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare diffuse cystic lung disease that affects young to middle-aged smoking adults of both genders. The identification of molecular alterations in the canonical mitogen-activated protein kinase (MAPK) signalling pathway in most specific lesions has demonstrated the clonal/neoplastic nature of PLCH. We will summarize the progress made in the understanding of the pathogenesis of adult PLCH, and briefly highlight the recent findings useful for the management of the patients. RECENT FINDINGS: The MAPK pathway is constantly activated in PLCH lesions. Apart from the BRAFV600E mutation, other driver somatic genomic alterations in this pathway (mainly MAP2K1  mutations/deletions and BRAF deletions) have been identified in the lesions, paving the way for targeted treatment. Smoking appears to promote the recruitment of MAPK-activated circulating myeloid precursors to the lung. The long-term survival of PLCH is more favourable with a 10-year survival >90%. Lung cancer and chronic respiratory failure are the main causes of death. Few patients develop severe pulmonary complications within the 5 years after diagnosis, justifying a close longitudinal follow-up of the patients. SUMMARY: PLCH is a MAPK driven neoplasia with inflammatory properties. The place of targeted therapies in severe forms of PLCH warrants further evaluation.

Long-term outcomes of adult pulmonary Langerhans cell histiocytosis: a prospective cohort.

BACKGROUND: The long-term outcomes of adult pulmonary Langerhans cell histiocytosis (PLCH), particularly survival, are largely unknown. Two earlier retrospective studies reported a high rate of mortality, which contrasts with our clinical experience. METHODS: To address this issue, all patients with newly diagnosed PLCH referred to the French national reference centre for histiocytoses between 2004 and 2018 were eligible for inclusion. The primary outcome was survival, which was defined as the time from inclusion to lung transplantation or death from any cause. Secondary outcomes included the cumulative incidences of chronic respiratory failure (CRF), pulmonary hypertension (PH), malignant diseases and extrapulmonary involvement in initially isolated PLCH. Survival was estimated using the Kaplan-Meier method. RESULTS: 206 patients (mean age 39±13 years, 60% female, 95% current smokers) were prospectively followed for a median duration of 5.1 years (IQR 3.2-7.6 years). Of these, 12 patients (6%) died. The estimated rate of survival at 10 years was 93% (95% CI 89-97%). The cumulative incidences of CRF and/or PH were <5% at both 5 and 10 years, and 58% of these patients died. 27 malignancies were observed in 23 patients. The estimated standardised incidence ratio of lung carcinoma was 17.0 (95% CI 7.45-38.7) compared to an age- and sex-matched French population. Eight (5.1%) of the 157 patients with isolated PLCH developed extrapulmonary involvement. CONCLUSION: The long-term prognosis of PLCH is significantly more favourable than has previously been reported. Patients must be closely monitored after diagnosis to detect severe complications early.

Sarcoidosis-Like Cancer-Associated Granulomatosis: Characteristics and a Case-Control Comparison with Sarcoidosis.

(1) Background: Systemic granulomatosis developed in a context of malignancy has already been reported. Our objective was to describe the clinical, radiological, functional, biological, and evolutive characteristics of sarcoidosis-like cancer-associated granulomatosis (SLCAG) and to compare them to those of sarcoidosis. (2) Methods: 38 patients with a biopsy-proven SLCAG developed after a diagnostic of malignancy were included. The control group consisted of sarcoidosis patients matched for age, sex, and radiologic stage. Clinical, biological, physiological, radiological, and outcome data were collected. (3) Results: The mean age of SLCAG patients was 51 ± 14 years. They were diagnosed within 15 ± 14 months of the cancer diagnosis (breast cancer most frequently). All SLCAG patients presented a thoracic involvement, extrathoracic locations were observed in 32% of subjects. SLCAG was more often asymptomatic than sarcoidosis (p < 0.0001). During follow-up, systemic treatment was less often required in SLCAG than in sarcoidosis (58% vs. 32%, p = 0.04 respectively) and SLCAG were characterized by a significantly less severe progression profile according to the Sarcoid Clinical Activity Classification, with a complete recovery more frequent at 5 years (p = 0.03). (4) Conclusion: This case-control study shows that SLCAG differs from sarcoidosis with a significantly more benign course. These results might argue for true differences in the physiopathology, which remain to be elucidated.

Vascular Ehlers-Danlos syndrome (vEDS): CT and histologic findings of pleural and lung parenchymal damage.

OBJECTIVES: To describe CT features of lung involvement in patients with vascular Ehlers-Danlos syndrome (vEDS), a rare genetic condition caused by pathogenic variants within the COL3A1 gene, characterized by recurrent arterial, digestive, and pulmonary events. MATERIAL AND METHODS: All consecutive vEDS patients referred to the national tertiary referral center for vEDS, between 2004 and 2016, were included. Chest CT scans obtained during the initial vascular work-up were reviewed retrospectively by two chest radiologists for lung involvement. Five surgical samples underwent histologic examination. RESULTS: Among 136 enrolled patients (83 women, 53 men; mean age 37 years) with molecularly confirmed vEDS, 24 (17.6%) had a history of respiratory events: 17 with pneumothorax, 4 with hemothorax, and 3 with hemoptysis that required thoracic surgery in 11. CT scans detected lung parenchymal abnormalities in 78 (57.3%) patients: emphysema (mostly centrilobular and paraseptal) in 44 (32.3%), comparable for smokers and non-smokers; clusters of calcified small pulmonary nodules in 9 (6.6%); and cavitated nodules in 4 (2.9%). Histologic examination of surgical samples found arterial abnormalities, emphysema with alveolar ruptures in 3, accompanied by diffuse hemorrhage and increased hemosiderin resorption. CONCLUSION: In vEDS patients, identification of lung parenchymal abnormalities is common on CT. The most frequently observed CT finding was emphysema suggesting alveolar wall rupture which might facilitate the diagnostic screening of the disease in asymptomatic carriers of a genetic COL3A1 gene mutation. The prognostic value and evolution of these parenchymal abnormalities remain to be evaluated. KEY POINTS: • Patients with vEDS can have lung parenchymal changes on top of or next to thoracal vascular abnormalities and that these changes can be present in asymptomatic cases. • The presence of these parenchymal changes is associated with a slightly higher incidence of respiratory events (although not statistically significant). • Identification of the described CT pattern by radiologists and chest physicians may facilitate diagnostic screening.

Clarifying the relationship between pulmonary langerhans cell histiocytosis and Alpha 1 antitrypsin deficiency.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking related, progressive diffuse cystic lung disease that occurs primarily in smokers. The aim of this study was to determine if there was an increase in alpha-1 antitrypsin deficient alleles or phenotypes in a large series of PLCH patients and whether serum alpha-1 antitrypsin levels correlated with markers of disease severity. Fifty PLCH patients, 24 with a diffuse cystic lung pattern and 26 with a typical nodulo-cystic pattern on imaging were included. The mean alpha-1 antitrypsin levels were in normal range for both the population with diffuse cystic lung pattern population (1.39 g/L ± 0.37) and the nodulo-cystic pattern group (1.41 g/L ± 0.21). Deficiency alleles PiZ and PiS were 1% and 2% respectively in the entire study population of 50 patients, demonstrating no increased incidence of alpha-1 antitrypsin deficiency in PLCH. Alpha-1 antitrypsin levels showed no correlation with lung function parameters or extent of cystic lesions on lung computed tomography.

Mitogen-activating protein kinase pathway alterations in Langerhans cell histiocytosis.

PURPOSE OF REVIEW: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the infiltration of involved tissues by specialized dendritic cells. The demonstration of the constant activation of the mitogen-activated protein kinase (MAPK) pathway in LCH lesions has been a breakthrough in the understanding of the pathogenesis of this rare disease. We will summarize the current knowledge on MAPK alterations in LCH and the new therapeutic options indicated by these findings. RECENT FINDINGS: Since the description of the B-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E mutation in LCH lesions, several other molecular alterations affecting the MAPK pathway have been identified in most cases. Based on these driver alterations, LCH cells were shown to be derived from hematopoietic precursors, which yielded the current concept of LCH as a myeloid inflammatory neoplasia. MAPK pathway inhibitors have emerged as an innovative therapy in severe forms of LCH, resulting in virtually no acquired resistance. However, although they are highly effective, their effect is only temporary, as the disease relapses upon discontinuation of the treatment. SUMMARY: LCH is an inflammatory myeloid neoplastic disorder, driven by mutations activating the MAPK pathway. MAPK-targeted treatments represent an important stepforward in the management of patients with severe progressive LCH.

Long-term survival following initiation of home non-invasive ventilation: a European study.

INTRODUCTION: Although home non-invasive ventilation (NIV) is increasingly used to manage patients with chronic ventilatory failure, there are limited data on the long-term outcome of these patients. Our aim was to report on home NIV populations and the long-term outcome from two European centres. METHODS: Cohort analysis including all patients established on home NIV from two European centres between 2008 and 2014. RESULTS: Home NIV was initiated in 1746 patients to treat chronic ventilatory failure caused by (1) obesity hypoventilation syndrome±obstructive sleep apnoea (OHS±OSA) (29.5%); (2) neuromuscular disease (NMD) (22.7%); and (3) obstructive airway diseases (OAD) (19.1%). Overall cohort median survival following NIV initiation was 6.6 years. Median survival varied by underlying aetiology of respiratory failure: rapidly progressive NMD 1.1 years, OAD 2.7 years, OHS±OSA >7 years and slowly progressive NMD >7 years. Multivariate analysis demonstrated higher mortality in patients with rapidly progressive NMD (HR 4.78, 95% CI 3.38 to 6.75), COPD (HR 2.25, 95% CI 1.64 to 3.10), age >60 years at initiation of home NIV (HR 2.41, 95% CI 1.92 to 3.02) and NIV initiation following an acute admission (HR 1.38, 95% CI 1.13 to 1.68). Factors associated with lower mortality were NIV adherence >4 hours per day (HR 0.64, 95% CI 0.51 to 0.79), OSA (HR 0.51, 95% CI 0.31 to 0.84) and female gender (HR 0.79, 95% CI 0.65 to 0.96). CONCLUSION: The mortality rate following initiation of home NIV is high but varies significantly according to underlying aetiology of respiratory failure. In patients with chronic respiratory failure, initiation of home NIV following an acute admission and low levels of NIV adherence are poor prognostic features and may be amenable to intervention.

Physiologic assessment before video thoracoscopic resection for lung cancer in patients with abnormal pulmonary function.

BACKGROUND: Impaired respiratory function may prevent curative surgery for patients with non-small cell lung cancer (NSCLC). Video-assisted thoracoscopic surgery (VATS) reduces postoperative morbility-mortality and could change preoperative assessment practices and therapeutic decisions. We evaluated the relation between preoperative pulmonary function tests and the occurrence of postoperative complications after VATS pulmonary resection in patients with abnormal pulmonary function. METHODS: We included 106 consecutive patients with ≤80% predicted value of presurgical expiratory volume in one second (FEV1) and/or diffusing capacity of carbon monoxide (DLCO) and who underwent VATS pulmonary resection for NSCLC from a prospective surgical database. RESULTS: Patients (64±9.5 years) had lobectomy (n=91), segmentectomy (n=7), bilobectomy (n=4), or pneumonectomy (n=4). FEV1 and DLCO preoperative averages were 68%±21% and 60%±18%. Operative mortality was 1.89%. Only FEV1 was predictive of postoperative complications [odds ratio (OR), 0.96; 95% confidence interval (CI), 0.926-0.991, P=0.016], but there was no determinable threshold. Twenty-five patients underwent incremental exercise testing. Desaturations during exercise (OR, 0.462; 95% CI, 0.191-0.878, P=0.039) and heart rate (HR) response (OR, 0.953; 95% CI, 0.895-0.993, P=0.05) were associated with postoperative complications. CONCLUSIONS: FEV1 but not DLCO was a significant predictor of pulmonary complications after VATS pulmonary resection despite a low rate of severe morbidity. Incremental exercise testing seems more discriminating. Further investigation is required in a larger patient population to change current pre-operative threshold in a new era of minimally invasive surgery.