More than 90% of cases of pulmonary Langerhans cell histiocytosis occur in cigarette smokers ranging from approximately 20 to 50 years of age. Men and women are about equally affected. The disease is probably underreported because many patients are asymptomatic and undergo spontaneous remission. About two thirds of patients present with symptoms attributable to smoking, such as dry cough, shortness of breath, and occasionally weight loss, fever, or night sweats; about 25% have no symptoms and are identified by abnormal routine chest radiographs; and about 10% to 20% present with spontaneous pneumothorax. Chest radiograph is often diagnostic and most commonly shows a pattern of reticulomicronodular infiltration involving both lungs, predominantly upper and middle lung fields with sparing of the costophrenic angles. Cysts are often identifiable within the infiltrates. With advanced disease, cyst formation is the most prominent radiologic feature. High-resolution computed tomography scan is typically incorporated into the patient’s workup and gives additional radiographic detail such as small poorly delimited nodules. Most patients show resolution of disease after smoking cessation; however, a few patients develop widespread honeycombing and ultimately succumb to their disease.

Wedge biopsy is generally employed in diagnosing pulmonary Langerhans cell histiocytosis; however, transbronchial biopsy may be diagnostic, and diagnostic yield has been reported at between 10% and 40% for transbronchial biopsies. Disease begins around small airways with an interstitial infiltrate of Langerhans cells. With disease progression, temporally heterogeneous, roughly symmetrical stellate nodules develop from the smaller infiltrates. The nodules contain varying numbers of eosinophils, fibroblasts, lymphocytes, and Langerhans cells—medium to large cells with convoluted, elongated, or folded pale nuclei with one or several small nucleoli and abundant pale pink cytoplasm. Langerhans cells are characteristically immunopositive with CD1a and S-100 and immunonegative with CD68. A desquamative interstitial pneumonia (DIP)-like accumulation of pigmented macrophages often is present in airspaces adjacent to the nodules. The mixed inflammatory infiltrate may be associated with adjacent pigmented macrophages; however, fragmented biopsies may not be diagnostic. Disease progression causes cyst formation within nodules and central scarring, with loss of Langerhans cells with progression of disease. Older lesions may coalesce, and ultimately emphysematous-like changes and honeycombing result.

The diagnosis of pulmonary Langerhans cell histiocytosis on transbronchial biopsy requires clinical and radiographic correlation. Differential diagnosis includes a cellular neoplasm and organizing pneumonia. Because various inflammatory conditions may contain scattered CD1a-positive Langerhans cells, diagnosis should be based predominantly on the characteristic histologic features, with immunostains performed to support the diagnosis. Advanced lesions consist of less cellular scars, so they will likely have few Langerhans cells, and therefore the immunostains may not be useful in confirming an advanced scarred lesion.