Pulmonary Langerhans Cell Histiocytosis
(Eosinophilic Granuloma; Pulmonary Granulomatosis X; Pulmonary Langerhans' Cell Granulomatosis; Histiocytosis X)
Pulmonary Langerhans cell histiocytosis (PLCH) is proliferation of monoclonal Langerhans cells in lung interstitium and airspaces. Etiology is unknown, but cigarette smoking plays a primary role. Symptoms are dyspnea, cough, fatigue, and pleuritic chest pain. Diagnosis is based on history and imaging tests and sometimes on bronchoalveolar lavage and biopsy findings. Treatment is smoking cessation. Corticosteroids are given in many cases, but efficacy is unknown. Lung transplantation is usually curative when combined with smoking cessation. Five-year survival is about 74%. Patients are at increased risk of cancer.
(See also Overview of Interstitial Lung Disease.)
PLCH is a disease in which monoclonal CD1a-positive Langerhans cells (a type of histiocyte) infiltrate the bronchioles and alveolar interstitium, accompanied by lymphocytes, plasma cells, neutrophils, and eosinophils. PLCH is one manifestation of Langerhans cell histiocytosis, which can affect organs in isolation (most notably the lungs, skin, bones, pituitary, and lymph nodes) or simultaneously. PLCH occurs in isolation ≥ 85% of the time.
The etiology of PLCH is unknown, but the disease occurs almost exclusively in whites 20 to 40 yr of age who smoke. Men and women are affected equally. Women develop disease later, but differences in age at onset by sex may represent differences in smoking behavior. Pathophysiology may involve recruitment and proliferation of Langerhans cells in response to cytokines and growth factors secreted by alveolar macrophages in response to cigarette smoke.
Typical symptoms and signs of PLCH are dyspnea, nonproductive cough, fatigue, fever, weight loss, and pleuritic chest pain. Ten percent to 25% of patients have sudden, spontaneous pneumothorax.
About 15% of patients are asymptomatic, with disease noted incidentally on a chest x-ray taken for another reason.
Bone pain due to bone cysts (18%), rash (13%), and polyuria due to diabetes insipidus (5%) are the most common manifestations of extrapulmonary involvement and occur in up to 15% of patients, rarely being the presenting symptoms of PLCH. There are few signs of PLCH; the physical examination results are usually normal.
PLCH is suspected based on history and chest x-ray and is confirmed by HRCT and bronchoscopy with biopsy and bronchoalveolar lavage.
Chest x-ray classically shows bilaterally symmetric nodular opacities in the middle and upper lung fields with cystic changes and normal or increased lung volumes. The lung bases are often spared. Appearance may mimic chronic obstructive pulmonary disease (COPD) or lymphangioleiomyomatosis.
Confirmation on HRCT of middle and upper lobe cysts (often with bizarre shapes) and/or nodules with interstitial thickening is considered diagnostic of PLCH.
Pulmonary function test findings are normal, restrictive, obstructive, or mixed depending on when the test is done during the course of the disease. Most commonly, the diffusing capacity for carbon monoxide (DLco) is reduced and exercise is impaired.
Bronchoscopy and biopsy are indicated when imaging and pulmonary function tests are inconclusive. Finding > 5% of CD1a cells in bronchoalveolar lavage fluid is highly suggestive of the disease. Biopsy shows proliferation of Langerhans cells with occasional clustering of eosinophils (the origin of the outdated term eosinophilic granuloma) in the midst of cellular and fibrotic nodules that may take on a stellate configuration. Immunohistochemical staining is positive for CD1a, S-100 protein, and HLA-DR antigens.
Spontaneous resolution of symptoms occurs in some patients with minimally symptomatic disease; 5-yr survival is about 75%, and median survival is 12 yr. However, some patients develop slowly progressive disease, for which the clinical markers include continued smoking, age extremes, multiorgan involvement, persistent constitutional symptoms, numerous cysts on chest x-ray, reduced DLco, low forced expiratory volume in 1 sec (FEV1)/ forced vital capacity (FVC) ratio (< 66%), high residual volume (RV)/total lung capacity (TLC) ratio (> 33%), and need for prolonged corticosteroid use. Cause of death is respiratory insufficiency or cancer. Lung cancer risk is increased because of cigarette smoking.
The main treatment is smoking cessation, which leads to symptom resolution in up to one third of patients.
Empiric use of corticosteroids and cytotoxic drugs is common practice even though their effectiveness is unproved.
Lung transplantation is an option for otherwise healthy patients with accelerating respiratory insufficiency, but the disorder may recur in the transplanted lung if the patient continues or resumes smoking.
In PLCH, monoclonal Langerhans cells proliferate in alveolar interstitium and bronchioles.
Consider PLCH in patients age 20 to 40 who smoke and in whom chest x-ray shows bilaterally symmetric nodular opacities in the middle and upper lung fields with cystic changes.
Confirm the diagnosis with HRCT or, if results are inconclusive, lung biopsy.
Recommend smoking cessation.
Consider corticosteroids and cytotoxic drugs and, if smoking has ceased, lung transplantation.