—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 5 - Langerhans Cell Histiocytosis
(Eosinophilic Granuloma; Langerhans Cell Granulomatosis)

Jeffrey L. Myers
Mayo Clinic
Rochester, MN


Click on each slide thumbnail image for an enlarged view
Clinical History
A 21 year old woman who recently quit smoking was self-referred for further evaluation of progressive shortness of breath due to diffuse interstitial lung disease. Transbronchial lung biopsy performed elsewhere was reported as "suspicious for" or "consistent with" Langerhans cell histiocytosis. While in an outpatient waiting area she developed increased back pain and resting sinus tachycardia. She was urgently admitted to a hospital cardiology service for further care and monitoring. Chest x-ray demonstrated left tension pneumothorax with mediastinal shift associated with diffuse interstitial infiltrates. A chest tube was placed. Cardiac evaluation demonstrated sinus tachycardia without evidence of intrinsic myocardial dysfunction. On the second hospital day she underwent video assisted thoracoscopic surgery with wedge lung biopsy and talc pleurodesis.


Case 4 - Figure 1 - Low magnification view showing eosinophilic material filling airspaces.
Case 4 - Figure 2 - Higher magnification photomicrograph showing the granular appearance of the airspace exudate. Note that the alveolar septa are only minimally thickened, and there is no significant inflammation.
Case 4 - Figure 3 - High magnification photomicrograph showing the coarsely granular nature of the intraalveolar eosinophilic material. The adjacent alveolar septa are normal except for mild hyperplasia of type 2 pneumocytes.

Diagnosis:
Langerhans cell histiocytosis (eosinophilic granuloma; Langerhans cell granulomatosis)

Discussion:
Langerhans cell histiocytosis (LCH), also termed pulmonary eosinophilic granuloma or Langerhans' cell granulomatosis, is an interstitial lesion of uncertain etiology characterized by an abnormal proliferation of modified histiocytes (Langerhans cells). While LCH shares some histologic features with the disseminated forms of histiocytosis X, it differs in that pulmonary involvement is the sole or predominant manifestation of disease.

LCH affects primarily young and middle-aged adults with a peak incidence in the third and fourth decades, and has been reported somewhat more commonly in men than women. Nearly all reported patients have been former or current cigarette smokers. Approximately 80% present with respiratory symptoms including nonproductive cough, dyspnea with exertion, and chest pain. Spontaneous pneumothorax is a commonly reported complication, but probably occurs in less than 25% of patients. A smaller percentage experience symptoms secondary to extrapulmonary involvement, mainly bone pain or diabetes insipidus. Chest roentgenograms characteristically show reticulonodular opacities, with or without honeycombing, involving predominantly the upper lobes. Sparing of the costophrenic angles is commonly seen. High resolution CT scans show a characteristic combination of cystic changes and nodules. Solitary pulmonary nodules are extraordinarily rare, having been reported on only two occasions. Other unusual manifestations include presentation as an intratracheal or intrabronchial tumor, and synchronous mediastinal lymph node involvement.

The natural history of LCH is difficult to predict and ranges from spontaneous regression to progressive respiratory insufficiency and death; overall mortality is probably around 10%. Older age at diagnosis and significant airflow limitation with air trapping may imply a worse prognosis. A subset of patients develop a degree of pulmonary hypertension that is out of proportion to the extent of pulmonary dysfunction for reasons not yet fully understood. Smoking cessation is the mainstay of therapy and should be strongly encouraged in all affected patients. Although corticosteroids are often used in symptomatic patients there is no scientifically sound evidence that they have a significant impact. Transplantation is a therapeutic option for patients with advanced disease, although LCH can recur within lung allografts. Several authors have suggested a relationship between pulmonary eosinophilic granuloma and bronchogenic carcinoma. It is likely that this relationship reflects a common risk factor (i.e. cigarette smoking) rather than cause-and-effect.

Pathologically, LCH is characterized by patchy interstitial nodules that often have a stellate configuration at low magnification. The nodules are distributed in a peribronchiolar fashion and may show central cavitation. Enlargement of adjacent air spaces (so-called paracicatricial airspace enlargement) is common. At higher magnification, the nodules contain a mixed inflammatory infiltrate including eosinophils, lymphocytes, plasma cells, and diagnostic histiocytes, so-called Langerhans cells. The proportion and number of inflammatory cell types contained within the nodules varies, and accurate diagnosis depends on recognition of the pathognomonic Langerhans cells. They have characteristic convoluted nuclei with bland evenly dispersed chromatin, inconspicuous nucleoli, and abundant eosinophilic cytoplasm with indistinct borders. The convoluted nuclei have a grooved appearance which distinguishes them from other histiocytes.

The diagnosis of LCH usually can be made on the basis of light microscopy alone. Transbronchial lung biopsies are relatively insensitive but can yield a specific diagnosis in some cases. Ultrastructurally Langerhans' cells contain unique pentilaminar inclusions (Birbeck or Langerhans' granules) within their cytoplasm, and for this reason electron microscopy was once considered the method of choice for establishing the diagnosis of LCH in difficult cases. Langerhans cells react with commercially available antibodies to S-100 protein and CD1a. Immunoreactivity for fascin, a 55-kd actin-bundling protein normally present in a subset of lymph node dendritic cells, has been demonstrated in non-lung specimens. Immunoperoxidase staining, a procedure that is easily applied to even small specimens, has thus become an important tool that largely replaces the need for electron microscopy in selected cases. The results of these procedures must be interpreted in the context of the clinical and pathologic findings, however, since Langerhans cells may be present in small numbers normally and may be increased in a variety of neoplastic and non-neoplastic lung conditions. Interestingly, increased numbers of Langerhans cells have also been demonstrated in cigarette smokers, providing additional evidence that LCH may be linked to cigarette smoking. There are two main theories of pathogenesis: 1) LCH represents some sort of non-neoplastic immune reaction to inhaled substances, and 2) LCH is a Langerhans cell neoplasm. The bulk of currently available data seems to favor the former, although the issue remains unresolved.

As the lesions of LCH become less cellular they also become more fibrotic and may be confused with the chronic interstitial pneumonias. It is imperative to distinguish these conditions because of marked differences in prognosis and treatment. At low magnification the first clue to the diagnosis of LCH is the stellate configuration and peribronchiolar distribution of the interstitial nodules. This contrasts with the diffuse and random distribution of the interstitial fibrosis in UIP. Alveolar spaces surrounding the nodules of LCH frequently contain clusters of lightly pigmented macrophages thus imparting a "DIP-like" appearance to the lesion. DIP differs from LCH in that the changes affect the interstitium in a diffuse and uniform manner. Eosinophilic pneumonia is predominantly an air space rather than an interstitial process, and is characterized by the presence of a mixture of eosinophils and macrophages within alveolar spaces. Reactive eosinophilic pleuritis (REP) is an unusual but nonspecific inflammatory response that occurs in about a third of patients with spontaneous pneumothorax. It is frequently mentioned in the differential diagnosis of LCH because the inflammatory infiltrate includes eosinophils and histiocytes. The majority of patients with REP, however, lack clinical, radiographic and pathologic evidence of interstitial lung disease and are unlikely to be confused with LCH.

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