Eosinophilic Granuloma, Thoracic

 

Background: Langerhans cell histiocytosis (LCH) describes a group of syndromes that share the common pathologic feature of infiltration of involved tissues by Langerhans cells. Typically, the skeletal system is involved, with a characteristic lytic bone lesion form that occurs in young children or a more acute disseminated form that occurs in infants. Pulmonary involvement is not unusual in systemic forms of LCH, but symptoms are rarely a prominent feature.

Localized pulmonary LCH (also termed pulmonary eosinophilic granuloma [EG]) is a rare pulmonary disease that occurs predominantly in young adults. The precise incidence and prevalence of pulmonary LCH are unknown, although studies of lung biopsy specimens from patients with interstitial lung disease identified pulmonary LCH in only 5%.

 

Pathophysiology: Pulmonary involvement in LCH is characterized by a granulomatous infiltration of the alveolar septa and bronchial walls by Langerhans cells that produce small, 1-5 mm nodules. The infiltrate can result in progressive lung destruction and widespread cystic change.

Langerhans cells are one part of the widespread system of "dendritic cells" that arise from bone marrow stem cells and normally are present in the lung. Cytoplasmic immunostaining with S100 antigen distinguishes them from histiocytes.

Other unique features of Langerhans cells are (1) the presence of Birbeck granules (rod-shaped intracellular structures identified by electron microscopy) and (2) the presence of CD1a antigen on the cell surface. As a result of these features, some authors prefer to term the disorder Langerhans cell "granulomatosis," since the Langerhans cell is not a member of the mononuclear phagocytic system (ie, not a macrophage or "histiocyte"). Since Langerhans cells may be identified in several pathologic pulmonary processes, the presence of pulmonary Langerhans cells is not diagnostic of pulmonary LCH.

 

Frequency:

  • In the US: LCH is rare and is responsible for only 3.4-5% of patients with chronic diffuse interstitial lung disease.
  • Internationally: See Frequency in the US.

Mortality/Morbidity: The course of pulmonary disease varies. Remission occurs in approximately 25-30% of patients, stabilization in 30-50%, and progression of the disease in 25-30%. Death from respiratory failure or cor pulmonale occurs in 5%.

Asymptomatic or minimally symptomatic patients tend to have the best outcomes. Decreased survival is associated with the following:

 

  • Diagnosis made at very young or very old age

     

  • Persistence of systemic symptoms

     

  • Recurrent pneumothoraces

     

  • Extrathoracic disease (except bone lesions)

     

  • Diffuse cystic lesions on chest radiograph

     

  • Lower forced expiratory volume in 1 second/forced vital capacity ratio at diagnosis

     

  • Higher respiratory volume/total lung volume ratio at diagnosis

     

  • Need for steroid therapy
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    Race: LCH usually affects whites. The disorder is rare in blacks.

    Sex: Male-to-female ratio is equal, although young men appear to have the worst prognosis.

    Age: Patients with isolated pulmonary EG usually are young adults aged 20-40 years.

    Clinical Details: A strong association exists between pulmonary LCH and smoking (90-95% of patients are smokers). Symptoms often improve with the cessation of smoking. No known genetic factors predispose patients to pulmonary LCH. Of LCH patients, 25-33% are asymptomatic at presentation.

    Symptomatic patients may present with the following:

     

  • Cough (66%)

     

  • Progressive dyspnea

     

  • Weight loss

     

  • Fever

     

  • Diabetes insipidus (25%)

     

  • Pneumothorax (10-25%)

     

  • Hemoptysis (<5%)
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    Pulmonary function tests do not provide consistent findings, but mild airway obstruction is common. A reduction in carbon monoxide diffusion capacity is present in 60-90% of patients. On bronchoalveolar lavage (BAL), an increased number of cells are seen, particularly macrophages; however, this may be a manifestation of the patient's smoking history. Langerhans cells also can be found on BAL. A diagnosis of pulmonary LCH is likely when the proportion of Langerhans cells in the BAL fluid is greater than 5%, although this finding is not specific for the disorder.

    A confident diagnosis of pulmonary LCH often can be made based on the patient's age, smoking history, and characteristic high-resolution CT findings, especially if patients are followed without treatment.

    When tissue confirmation is required, make the diagnosis using open lung biopsy via video-assisted thoracoscopy. Transbronchial biopsy has a low diagnostic yield (10-40%) because of the patchy nature of the disease and the small amounts of tissue obtained.

    Treatment

    Treatment consists of the cessation of smoking, which stabilizes symptoms in most patients. Corticosteroids are used in progressive or systemic disease. Cytotoxic agents (eg, cyclophosphamide) can be employed for patients who do not respond to smoking cessation and steroids. No treatment has been confirmed useful, and no double-blind therapeutic trials have been reported.

    Lung transplantation also has been performed for treatment of LCH. No specific criteria exist for determining which pulmonary LCH patients are candidates for lung transplantation. Patients with rapidly declining lung function, severe pulmonary symptoms, and a lack of response to other treatments are the best candidates for transplant consideration; however, the disorder may recur in the transplanted lung.

    Etiology

    Etiology of the disorder is not known. The bronchocentricity and the tendency of the disease to regress following the cessation of smoking suggest a reactive immune response in the bronchioles to an inhaled antigen in cigarette smoke that is mediated by the Langerhans cell system. The recurrence of the disease after transplantation suggests that extrapulmonary factors also are involved in disease pathogenesis or that the condition may represent a neoplastic disorder.

    An association between EG and lymphoma has been described. Bronchogenic carcinoma has been identified with increased frequency in patients with pulmonary LCH. Lung scarring and smoking may contribute to the development of lung cancer in these patients. Although intriguing, evidence likely is insufficient to either prove or refute the association between pulmonary LCH and malignant neoplasms.

    Preferred Examination: In patients with suggested EG, obtain a chest radiograph and high-resolution chest CT.

    DIFFERENTIALS


    Other Problems to be Considered:

    The differential diagnosis depends on the stage of the disorder.

    When only small nodules are identified, consider the following:
    Granulomatous infections (eg, tuberculosis, fungi)
    Other infections (eg, varicella; however, nodules usually are poorly defined)
    Other granulomatous disorders (eg, sarcoid)
    Pneumoconiosis (eg, silicosis, coal workers pneumoconiosis)
    Neoplasm (eg, metastatic disease)

    When both nodules and small cysts are present, consider the following:
    Lymphocytic interstitial pneumonitis
    Neoplasm (eg, cavitary metastases)
    Any nodular disease with coexistent emphysema

    When only cysts are present, consider the following:
    Lymphangioleiomyomatosis
    Chronic Pneumocystis carinii pneumonia with cyst formation
    Central acinar emphysema

    Increased lung volumes with interstitial disease, consider the following:
    Pulmonary LCH
    Emphysema with concomitant interstitial disease
    Lymphangioleiomyomatosis
    Cystic fibrosis (produces "interstitial" appearance)
    Acute interstitial infiltrate

     

    X-RAY

    Findings: Chest radiographs are normal in fewer than 10% of patients.

     

  • Usually, diffuse reticulonodularity (3- to 10-mm nodules that may cavitate) is observed in a symmetric upper lobe predominance (bases tend to be spared), with preservation of lung volumes.

     

  • Associated pneumothorax is found in 15-25% of patients.

     

  • Pleural effusion is rare.

     

  • In the late stage, diffuse cysts may be found that spare only the costophrenic angles.
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    CAT SCAN

    Findings: On high-resolution chest CT, the distribution of the disease is similar to that seen on chest radiograph with an upper lobe predominance. Findings include the following:

     

  • Centrilobular opacities

     

  • Small nodules (1-5 mm, may be up to 1.5 cm)

     

  • Cystic cavitation of small nodules

     

  • Cysts (initially thick walled, later thin walled; typically, lesions progress in this way)
    •

    Some authors believe that nodules do not cavitate and cysts represent a paracicatricial emphysematous change adjacent to nodules. Cysts usually are smaller than 10 mm, although cysts larger than 10 mm are found in more than 50% of patients. Cyst walls usually are thin (less than 1 mm) but can vary, and the cysts are not necessarily round (may be bilobed, branching). The intervening lung parenchyma appears normal.

    In the late stages, diffuse cysts may be seen, with no nodules evident (approximately 20% of patients), while in the early stages, only nodules may be seen. In the late stages, the disorder may be indistinguishable from lymphangiomyomatosis; however, sparing of the costophrenic angles suggests the diagnosis of eosinophilic granuloma. Mediastinal adenopathy has been described in some series but usually is uncommon. Other authors report mediastinal adenopathy in as many as 30% of patients.

    Degree of Confidence: A diagnosis of pulmonary EG can be established with a high degree of confidence when small nodules and cysts are seen in a young patient with a history of smoking.

     

    MRI

    Findings: MRI does not contribute to the evaluation of this disorder.

    ULTRASOUND

    Findings: Ultrasound does not contribute to the evaluation of this disorder.

    NUCLEAR MEDICINE

    Findings: Gallium-67 scans usually are negative.

    PICTURES

     

    Caption: Picture 1. Chest CT in a patient with pulmonary eosinophilic granuloma demonstrates scattered cavitary and noncavitary nodules.
    Picture Type: CT