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Eosinophilic Granuloma (Histiocytosis X): Differential Diagnoses & Workup

Author: Eleanor M Summerhill, MD, Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Warren Alpert Medical School of Brown University; Director of Internal Medicine Residency Program, Memorial Hospital of Rhode Island
Contributor Information and Disclosures

Updated: Mar 3, 2008

Differential Diagnoses

Other Problems to Be Considered

• Tuberous sclerosis
• Lymphangioleiomyomatosis (LAM): Patients with PLCH frequently present to medical attention with spontaneous pneumothoraces. Lymphangioleiomyomatosis is a disorder that exclusively affects young women and is characterized by cystic, emphysematous dilation of the terminal airways and shares this predisposition. It may be mistaken for PLCH on a chest radiograph or high-resolution CT (HRCT) scan of the chest.

Workup

Laboratory Studies

• Results from routine laboratory testing are nonspecific.
• Peripheral eosinophilia is not observed.

Imaging Studies

• Chest radiographs characteristically reveal bilateral, symmetric, ill-defined nodules and reticulonodular infiltrates. As the disease progresses, cystic lesions appear. An upper-zone predominance of radiographic findings with sparing of the costophrenic angles is typically observed.
  • Cystic lesions can be of various sizes and thin or thick walled.
  • Lung volume is normal or increased.
  • Honeycombing indicates advanced disease.
  • Bony lesions may occur on the ribs or any other site.
  • Hilar or mediastinal adenopathy is rare and should prompt the consideration of sarcoidosis or malignancy.
  • Pleural effusion is uncommon.
• HRCT of the chest may be virtually diagnostic in the appropriate clinical setting. Pathognomonic findings include nodules and cysts, predominantly in the mid and upper lung zones, with sparing of the costophrenic regions. The nodules may be cavitary and variable in size. Likewise, the cysts may be of various diameters and wall thicknesses. A broad differential diagnosis must be considered in the following situations:
  • If only nodules are present on HRCT, the findings are nonspecific, and a number of other granulomatous disorders cannot be excluded radiographically.
  • When cysts are an isolated finding, LAM must be considered as well. Unlike PLCH, LAM is usually uniformly distributed throughout the lungs. Sparing of the costophrenic angles supports a diagnosis of PLCH.
  • Emphysema is usually distinguishable, as walls do not surround the cystic spaces found in emphysema. However, extensive emphysema is sometimes difficult to differentiate from PLCH.

Other Tests

• Pulmonary function testing can demonstrate all patterns of abnormality: Normal, restrictive, obstructive, or mixed.
  • Most patients have normal or near-normal total lung capacity with near-normal spirometry findings.
  • Gas exchange, as measured by the diffusing capacity for carbon monoxide, is generally reduced.
  • In rare cases, patients have reversible airflow limitation.
• Gas exchange abnormalities may be present at rest. Although such abnormalities are most pronounced with exercise, most patients have a normal gradient of alveolar-arterial partial pressures.
• Pulmonary exercise testing may demonstrate decreased exercise capacity with reduced oxygen utilization. Gas exchange, ventilatory, and pulmonary vascular abnormalities may also be present. Therefore, exercise limitation is generally multifactorial.

Procedures

• Analysis of bronchioalveolar lavage (BAL) fluid is sometimes diagnostic.
  • A greater than 5% increase in the number of Langerhans cells in BAL specimens is almost pathognomonic for PLCH. Although this finding is highly specific, it is not particularly sensitive.
  • Langerhans cells can be recognized by their characteristic staining for S-100 protein or peanut agglutination antigen.
  • These cells are CD1a-positive, and may also be identified by a specific monoclonal antibody (MT-1).
• Although the disease is present in a patchy distribution, sometimes transbronchial biopsy may be diagnostic if sampling is done in a number of areas and sufficient tissue is obtained.
  • Immunostaining for Langerhans cells (CD1a) improves the sensitivity and specificity of the biopsy sample.
  • The diagnostic yield is approximately 10-40%.
• Open or thoracoscopic lung biopsy is the most sensitive and specific diagnostic modality, and is generally recognized as the criterion standard.
  • In addition to immunostaining, electron microscopy of tissue samples may be performed.
  • Langerhans cells demonstrate the characteristic intracytoplasmic Birbeck granules. These are found in all Langerhans cells, but they are present in increased numbers in the pathologic Langerhans cells found in the lesions of PLCH.

Histologic Findings

The earliest lesions consist of Langerhans cells grouped around the small airways. These inflammatory lesions expand to form granulomatous nodules composed of Langerhans cells as well as eosinophils, macrophages, lymphocytes, plasma cells, and fibroblasts.

In addition to looking for the typical morphologic features of Langerhans cells, immunostaining for S-100 and CD1a may also be useful. Electron microscopy helps in identifying Langerhans cells by demonstrating the presence of diagnostic pentilaminar cytoplasmic inclusion bodies, or Birbeck granules (x-bodies).

Of note, eosinophils may not always be present. Therefore, the name eosinophilic granuloma, despite being a commonly accepted term, is a misnomer.

Granulomas are centered on distal bronchioles. Evidence of pulmonary vascular involvement and respiratory bronchiolitis are often present, as well as infiltration and destruction of airway walls. As the disease progresses, cavitation occurs as a result of this destruction. The nodule fibroses, eventually forming a stellate scar.

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