—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 2 - Langerhans Cell Histiocytosis (Eosinophilic Granuloma; Langerhans Cell Granulomatosis)

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
This 38-year-old man presented for evaluation of persistent non-productive cough and increasing shortness of breath with exertion. He was first seen approximately 9 months prior to admission for evaluation of an abnormal chest radiograph. At that time his PA chest film and CT scan were described as showing numerous small nodular opacities throughout both lungs with bilateral hilar adenopathy. Repeat CT scan showed diffuse bilateral faintly nodular infiltrates with predominantly upper lung cystic changes and mild mediastinal and hilar adenopathy. He continued to smoke one pack of cigarettes per day as he had for approximately 20 years. He underwent video assisted thoracoscopic lung biopsy.

Microscopic Description:


Case 2 - Figure 1 - Low magnification photomicrograph showing a stellate nodule with associated enlargement of surrounding air spaces ("paracicatricial airspace enlargement").
Case 2 - Figure 2 - Higher magnification photomicrograph showing expansion of interstitium by a mixed population of mainly mononuclear cells. Extension of the polymorphic infiltrate from peribronchiolar interstitium into contiguous alveolar septa results in the stellate configuration illustrated in Figure 1.
Case 2 - Figure 3 - High magnification photomicrograph demonstrating Langerhans cells. Langerhans cells closely resemble histiocytes and are distinguished by their irregular, highly convoluted nuclear contours.

At low magnification, the main changes in sections from this thoracoscopic lung biopsy is the presence of partially fibrotic, stellate nodules centered on bronchioles. The bronchiolocentric nodules are variably cellular, tending to be most cellular at the periphery. At higher magnification the polymorphic infiltrate comprises lymphocytes, plasma cells, eosinophils, and modified histiocytes referred to as Langerhans cells. The Langerhans cells can be distinguished by their highly convoluted nuclear contours, nuclear grooves, and abundant cytoplasm.

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 LCH 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 are 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 favors the former.

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 more 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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