Pulmonary Langerhans Cell Histiocytosis

Cecilia M. Smith and Gordon L. Yung

Pulmonary Langerhans cell histiocytosis (PLCH), also known as histiocytosis X, is a diffuse interstitial lung disease characterized histologically by a predominance of differentiated cells of the monocytes/macrophage lineage. The term PLCH is preferred over other names such as eosinophilic granuloma or Langerhans cell granulomatosis. These are both misnomers because the pathologic lesions contain few, if any, eosinophils and do not form true granulomas. PLCH shares a spectrum of disease with Letterer–Siwe disease and Hand–Schüller–Christian disease. The latter two diseases have characteristic ages of onset (typically childhood), are more severe, and affect multiple organs including bone and, occasionally, soft tissues with infiltration of atypical histiocytes. Although PLCH was initially described as a disease of bone, isolated lung disease and multisystem involvement are well described.

The incidence and prevalence of PLCH are unknown. However, it is diagnosed rarely, even at centers that specialize in diffuse interstitial pulmonary disease. PLCH may occur at any age. It has been reported as early as infancy (3 months of age) and up to the seventh decade; however, most cases are diagnosed in young adulthood, between 20 and 40 years of age. PLCH was previously believed to affect men more than women, but recent data do not support a gender predilection. Women tend to develop the disease at a later age than men. Caucasians appear to be affected more commonly than those of African and Asian descent. There is no associated occupational predisposition. The most striking demographic feature of the disease is its strong association with current or past tobacco use. Fewer than 5% of patients are lifelong nonsmokers.

CLINICAL PRESENTATION

Although patients with PLCH often present with pulmonary (cough, dyspnea, chest pain) or constitutional (fever, weight loss) symptoms, some present with asymptomatic radiographic findings. The most common abnormal radiographic presentation is spontaneous pneumothorax. Hemoptysis may occasionally occur, but this should prompt a search for opportunistic infections (especially Aspergillus spp.) or associated tumor. Painful bony lesions may precede lung involvement and result in pathologic fracture as a presenting symptom. There are no diagnostic findings on bone radiographs. Diabetes insipidus may occur as a result of hypothalamic involvement and probably portends a poor prognosis. Airway involvement, pleural effusion, and lymphadenopathy are distinctly uncommon manifestations.

The physical examination is often normal. Crackles and finger clubbing are uncommon; however, in advanced disease, evidence of pulmonary hypertension with associated right-heart failure may be present. Laboratory evaluation is typically normal. Peripheral eosinophilia is not associated with PLCH. Although spirometry and static lung volumes are often normal, obstructive or restrictive patterns may be seen and the diffusing capacity of the lung for carbon monoxide (DLCO) is characteristically reduced. Obstructive airway disease with hyperinflation occurs in a minority of patients with advanced cystic disease. There is usually exercise intolerance with activity limitation out of proportion to pulmonary function impairment. Resting room air arterial blood gas measurements are typically normal until disease is advanced, but exercise testing may reveal gas exchange abnormalities as well as a reduction in maximum oxygen consumption and workload.

DIAGNOSIS

The diagnosis of PLCH is strongly suggested by typical findings on the chest radiograph and high-resolution computed tomography (HRCT) scan. Specifically, small (2–12 mm) stellate nodules, upper-lobe reticulonodular opacities, and cysts or honeycombing favoring the upper lung zones are strongly suggestive. Differential diagnosis of similar radiologic findings might include lymphangioleiomyomatosis, tuberous sclerosis, hypersensitivity pneumonitis, chronic eosinophilic pneumonia, sarcoidosis, and end-stage idiopathic pulmonary fibrosis. In the appropriate clinical setting (i.e., young smokers), these findings may be pathognomonic. HRCT scanning can detect disease not readily apparent on the chest radiograph and is extremely useful in monitoring disease progression and response to therapy. Radiographic findings include upper lung zone predominance characteristically sparing the costophrenic angles, reticulonodular opacities, ill-defined or stellate nodules (2–12 mm size), upper-zone cysts, and honeycomb lung with preservation of lung volume. Patients with costophrenic angle involvement are more likely to experience disease progression and have an unfavorable prognosis.

The Langerhans cell, the pathologic cell type involved in PLCH, is derived from the monocyte/macrophage lineage and is characterized by pale cytoplasm and a large nucleus with prominent nucleoli. Pentalaminar cytoplasmic inclusions seen on electron microscopy are known as Birbeck granules or X bodies, and are considered pathognomonic. Immunohistochemical stains are positive for S100 and CD1a. These cells are normally found scattered in the dermis, lung, pleura, and reticuloendothelial system. Small numbers may also be seen in the pulmonary parenchyma of patients with idiopathic pulmonary fibrosis. Immunostaining and identification of the S100 protein or CD1a receptor on pathologic specimens usually obviate the need for electron microscopy.

Only gold members can continue reading. Log In or Register to continue